Methods of treating traumatic brain injury using pro-neurogenic compounds

ABSTRACT

This invention relates generally to stimulating neurogenesis (e.g., post-natal neurogenesis, e.g., post-natal hippocampal neurogenesis) and protecting from neuron cell death.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/832,056, filed on Jul. 7, 2010, which is a continuation-in-part ofU.S. application Ser. No. 12/685,652, filed on Jan. 11, 2010, whichclaims the benefit and priority to U.S. Provisional Application No.61/143,755, filed on Jan. 9, 2009; each of these prior applications isincorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under Grant5DP1OD00027605, 5R37MH05938809, and 1RO1MH087986, which were awarded bythe National Institute of Health; the Government has certain rights inthe invention.

FIELD OF THE INVENTION

This invention relates generally to the discovery of pro-neurogeniccompounds capable of promoting neurogenesis and/or reducing neuronalcell death.

BACKGROUND OF THE INVENTION

It is now accepted that the adult vertebrate brain fosters the birth andfunctional incorporation of newly formed neurons (Goldman and Nottebohm,1984; Paton and Nottebohm, 1984; Burd and Nottebohm, 1985). However, itwas long thought that no new neurons could be added to the adultmammalian brain. This dogma was challenged in the 1960's whenautoradiographic evidence of new neuron formation in the hippocampaldentate gyms, olfactory bulb, and cerebral cortex of the adult rat waspresented (Altman, 1962, 1963; Altman and Das, 1965, 1966a,b). It is nowaccepted that within all mammalian species, including humans (Erikssonet al., 1998), there are two major reservoirs of neuronal stem cells,one located in the subgranular zone (SGZ) of the hippocampal dentategyms and another in the subventricular zone (SVZ) (Gross, 2000). Neuralstem cells in the SVZ facilitate formation of new neurons that migraterostrally to populate the olfactory bulb, while neural stem cells in theSGZ produce neurons that integrate locally in the granular layer of thedentate gyms, a region of the hippocampus that exhibits lifelongstructural and functional plasticity.

The process of new neuron formation in the adult mouse brain can beinfluenced by environmental, chemical and genetic variables. Asdemonstrated by Gage and colleagues, neurogenesis in the adult mousebrain is enhanced when animals are exposed to an enriched environment(Kempermann et al., 1998) or able to exercise voluntarily (van Praag etal., 1999). More recently, anti-depressant drugs have been shown toenhance levels of adult neurogenesis in animals, including humans(Schmidt and Duman, 2007; Boldrini et al., 2009). Among many genesreported to impact adult neurogenesis is the gene encoding neuronal PASdomain protein 3 (NPAS3), a central nervous system (CNS)-specifictranscription factor that has been associated with schizophrenia andbipolar disorder (Kamnsasaran et al., 2003; Pickard et al., 2005, 2006,2009; Lavedan et al., 2008). Animals missing both copies of the NPAS3gene suffer a profound loss of adult hippocampal neurogenesis coupledwith significant behavioral deficits (Pieper et al., 2005). Knowing thatimpaired post-natal neurogenesis elicits unfavorable phenotypicdeficits, it is predicted that pro-neurogenic chemical compounds shouldexhibit favorable therapeutic benefits.

SUMMARY OF THE INVENTION

This invention relates generally to compounds that promote thegeneration or the survival of existing neurons in the mammalian brain.For the purpose of simplicity we refer to these compounds as beingpro-neurogenic. In certain embodiments, the compounds promote thegeneration or survival of neurons in the post-natal mammalian brain. Incertain embodiments, the compounds promote the survival, growth,development and/or function of neurons, particularly CNS, brain,cerebral, and hippocampal neurons. In certain embodiments, the compoundsstimulate post-natal hippocampal neurogenesis, which while not wishingto be bound by theory, is believed to represent a therapeutic target fora variety of neuropsychiatric and neurodegenerative diseases, including(but not limited to) schizophrenia, major depression, bipolar disorder,normal aging, epilepsy, traumatic brain injury, post-traumatic stressdisorder, Parkinson's disease, Alzheimer's disease, Down syndrome,spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington'sdisease, stroke, radiation therapy, chronic stress, and abuse ofneuro-active drugs, such as alcohol, opiates, methamphetamine,phencyclidine, and cocaine. The invention also features compositions(e.g., pharmaceutical compositions) that include such compounds as wellas methods of making, identifying, and using such compounds. Otherfeatures and advantages are described in, or will be apparent from, thepresent specification and accompanying drawings.

Accordingly, in one aspect, methods for promoting post-natal mammalianneurogenesis and/or reducing neuronal cell death in a subject in needthereof are described, the method comprising administering an effectiveamount of a compound having formula (I) or a pharmaceutically acceptablesalt thereof:

wherein:

each of R¹, R², R³, and R⁴ is independently selected from hydrogen,halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkynyl, cyclopropyl, —N₃, cyano, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and nitro;

R and R′ are defined according to (1), (2), (3), (4), or (5) below:

(1) R and R′ together with C₂ and C₃, respectively, form a fused phenylring having formula (II):

wherein each of R⁵, R⁶, R⁷, and R⁸ is independently selected fromhydrogen, halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy,C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₂-C₆ alkynyl, cyclopropyl, —N₃, cyano, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and nitro; OR

(2) each of R and R′ is, independently, hydrogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl; OR

(3) R and R′ together with C₂ and C₃, respectively, form a fusedheterocyclic ring containing from 5-6 ring atoms, wherein from 1-2 ofthe ring atoms is independently selected from N, NH, N(C₁-C₆ alkyl),NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclic ring isoptionally substituted with from 1-3 independently selected R^(a); OR

(4) R and R′ together with C₂ and C₃, respectively, form a fused C₅-C₆cycloalkyl ring that is optionally substituted with from 1-4independently selected R^(a); OR

(5) R and R′ together with C₂ and C₃, respectively, form a fusedheteroaryl ring containing from 5-6 ring atoms, wherein from 1-2 of thering atoms is independently selected from N, NH, N(C₁-C₃ alkyl), O, andS; and wherein said heteroaryl ring is optionally substituted with from1-3 independently selected R^(b);

L¹ is:

-   -   (i) C₁-C₃ straight chain alkylene, which is optionally        substituted with from 1-2 independently selected R^(c); or    -   (ii) a bond that directly connects N in the 5-membered ring of        formula (I) to A in formula (I);

L² is:

-   -   (i) C₁-C₃ straight chain alkylene, which is optionally        substituted with from 1-2 independently selected R^(c); or    -   (ii) a bond that directly connects A in formula (I) to Z in        formula (I);

A is:

-   -   (i) CR^(A1)R^(A2), wherein each of R^(A1) and R^(A2) is        independently selected from hydrogen, halo, C₁-C₃ alkyl, or OR⁹;        or    -   (ii) C═O; or    -   (iii) C₃-C₅ cycloalkylene that is (a) substituted with 1 oxo;        and (b) optionally further substituted with from 1-4        independently selected R^(a); or    -   (iv) heterocycloalkylene containing from 3-5 ring atoms, wherein        from 1-2 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heterocycloalkylene        is (a) substituted with 1 oxo; and (b) is optionally further        substituted with from 1-4 independently selected R^(a);

Z is:

-   -   (i) —NR¹⁰R¹¹; or    -   (ii) —C(O)NR¹⁰R¹¹; or    -   (iii) —OR¹²; or    -   (iv) —S(O)_(n)R¹³, wherein n is 0, 1, or 2 or    -   (v) heterocycloalkenyl containing from 5-6 ring atoms, wherein        from 1-3 of the ring atoms is independently selected from N, NH,        N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S; and wherein said        heterocycloalkenyl is optionally substituted with from 1-4        independently selected R^(a);    -   (vi) C₆-C₁₀ aryl that is optionally substituted with from 1-4        independently selected R^(b); or    -   (vii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4 independently selected        R^(b); or    -   (viii) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (ix) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a); or    -   (x) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (xi) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

R⁹ is hydrogen; or C₁-C₃ alkyl that is optionally substituted withhydroxyl or C₁-C₃ alkoxy;

each of R¹⁰ and R¹¹ is independently selected from the substituentsdelineated collectively in (a) through (k) below:

-   -   (a) hydrogen;    -   (b) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b);    -   (c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6        of the ring atoms is independently selected from N, NH, N(C₁-C₃        alkyl), O, and S; and wherein said heteroaryl is optionally        substituted with from 1-4R^(b);    -   (d) C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is optionally        substituted with from 1-3R^(d);    -   (e) —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆ haloalkyl), or —C(O)O(C₁-C₆        alkyl);    -   (f) C₂-C₆ alkenyl or C₂-C₆ alkynyl;    -   (g) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   (h) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   (i) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   (j) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   (k) C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, each of which is        optionally substituted with from 1-4 independently selected        R^(a); and    -   (l) C₇-C₁₂ aralkyl, wherein the aryl portion is optionally the        aryl portion from is optionally substituted with from 1-4        independently selected R^(b),

R¹² is:

-   -   (i) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b); or    -   (ii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4R^(b); or    -   (iii) C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is        optionally substituted with from 1-3R^(d); or    -   (iv) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (v) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (vi) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (vii) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

R¹³ is:

-   -   (i) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b); or    -   (ii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4R^(b);    -   (iii) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (iv) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (v) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (vi) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

R^(a) at each occurrence is, independently selected from halo, hydroxyl,C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy,oxo, thioxo, ═NH, ═N(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, —NH₂,—NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and cyano;

R^(b) at each occurrence is independently selected from the substituentsdelineated in (aa) through (dd) below:

-   -   (aa) C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆        thiohaloalkoxy; —O—(CH₂)₁₋₃—[O(CH₂)₁₋₃]₁₋₃—H; —C₁-C₆ alkyl,        C₁-C₆ haloalkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,        —NHC(O)(C₁-C₆ alkyl), wherein the alkyl portion of each is        optionally substituted with from 1-3 independently selected        R^(e);    -   (bb) halo; hydroxyl; cyano; nitro; —NH₂; azido; sulfhydryl;        C₂-C₆ alkenyl; C₂-C₆ alkynyl; —C(O)H; —C(O)(C₁-C₆ alkyl);        —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl); —C(O)NH₂;        —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);        —SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂;    -   (cc) C₃-C₆ cycloalkyl or heterocyclyl containing from 5-6 ring        atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is        independently selected from N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆        alkyl), O, and S; and wherein each of said phenyl and        heterocyclyl is optionally substituted with from 1-3        independently selected R^(a); and    -   (dd) phenyl or heteroaryl containing from 5-6 ring atoms,        wherein from 1-2 of the ring atoms of the heteroaryl is        independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;        wherein each of said phenyl and heteroaryl is optionally        substituted with from 1-3 substituents independently selected        from halo; hydroxyl; cyano; nitro; —NH₂; —NH(C₁-C₆ alkyl),        N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), C₁-C₆ alkoxy; C₁-C₆        haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆ thiohaloalkoxy; C₁-C₆ alkyl,        and C₁-C₆ haloalkyl;

R^(c) at each occurrence is, independently selected from halo, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano;

R^(d) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂₅—NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano; and

R^(e) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy; C₁-C₆ thioalkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thiohaloalkoxy; —NH₂;—NH(C₁-C₆ alkyl); N(C₁-C₆ alkyl)₂; —NHC(O)(C₁-C₆ alkyl); cyano; —C(O)H;—C(O)(C₁-C₆ alkyl); —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl);—C(O)NH₂; —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);—SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂; and L³-(C₁-C₆alkylene)-Cy, where in L³ is a —O—, —NH—, —NCH₃—, —C(O)—,

—C(O)NH—, —C(O)NCH₃—, —NHC(O)—, or —NCH₃C(O)—, and Cy is a saturated,partially unsaturated or aromatic carbocyclic or heterocyclic ringsystem;

or a pharmaceutically acceptable salt thereof.

In some embodiments, one or more of (A), (B), or (C) apply.

(A) Provided that when R and R′ are defined according to definition (3),then:

(i) each of L¹ and L² must be C₁-C₃ alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c) when A is CH₂; or

(ii) Z must be other than heteroaryl containing from 5-14 (e.g., 5-6 or6) ring atoms, wherein from 1-6 of the ring atoms is independentlyselected from N, NH, N(C₁-C₃ alkyl), O, and S; and wherein saidheteroaryl is optionally substituted with from 1-4 independentlyselected R^(b); e.g., other than substituted pyridyl, e.g., other thanpyridyl substituted with C₁-C₃ alkyl (e.g., CH₃), e.g., other than 2 or6-methylpyridyl.

(B) Each of R¹⁰ and R¹¹ cannot be optionally substituted naphthyl (e.g.,each of R¹⁰ and R¹¹ cannot be unsubstituted naphthyl). In embodiments,each of R¹⁰ and R¹¹ is other than optionally substituted naphthyl (e.g.,unsubstituted naphthyl) when R and R′ are defined according todefinitions (1), (2), and (4); and A is CR^(A1)R^(A2) (e.g., CHOR⁹,e.g., CHOH), and each of L¹ and L² is C₁-C₃ alkylene (e.g., each of L¹and L² is CH₂).

(C) R¹² and/or R¹³ cannot be substituted phenyl. In embodiments, R¹²and/or R¹³ cannot be substituted phenyl when R and R′ are definedaccording to definition (1); and A is CR^(A1)R^(A2) (e.g., CHOR⁹, e.g.,CHOH), and each of L¹ and L² is C₁-C₃ alkylene (e.g., each of L¹ and L²is CH₂).

In some embodiments, (A), (B), or (C) applies. In other embodiments, (A)and (B); or (A) and (C); or (B) and (C) applies. In still otherembodiments, (A), (B), and (C) apply.

In another aspect, methods for promoting post-natal mammalianneurogenesis in a subject in need thereof are featured. The methodincludes administering to the subject an effective amount of a compoundhaving formula (I) or a pharmaceutically acceptable salt thereof

wherein:

each of R¹, R², R³, and R⁴ is independently selected from hydrogen,halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, cyano,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), andnitro;

R and R′ are defined according to (1), (2), (3), (4), or (5) below:

(1) R and R′ together with C₂ and C₃, respectively, form a fused phenylring having formula (II):

wherein each of R⁵, R⁶, R⁷, and R⁸ is independently selected fromhydrogen, halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy,C₁-C₆ haloalkoxy, C₁-C₆ halothioalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl,cyano, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl),and nitro; OR

(2) each of R and R′ is, independently, hydrogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl; OR

(3) R and R′ together with C₂ and C₃, respectively, form a fusedheterocyclic ring containing from 5-6 ring atoms, wherein from 1-2 ofthe ring atoms is independently selected from N, NH, N(C₁-C₆ alkyl),NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclic ring isoptionally substituted with from 1-3 independently selected R^(a); OR

(4) R and R′ together with C₂ and C₃, respectively, form a fused C₅-C₆cycloalkyl ring that is optionally substituted with from 1-4independently selected R^(a); OR

(5) R and R′ together with C₂ and C₃, respectively, form a fusedheteroaryl ring containing from 5-6 ring atoms, wherein from 1-2 of thering atoms is independently selected from N, NH, N(C₁-C₃ alkyl), O, andS; and wherein said heteroaryl ring is optionally substituted with from1-3 independently selected R^(b);

L¹ is:

-   -   (i) C₁-C₃ straight chain alkylene, which is optionally        substituted with from 1-2 independently selected R^(c); or    -   (ii) a bond that directly connects N in the 5-membered ring of        formula (I) to A in formula (I);

L² is:

-   -   (i) C₁-C₃ straight chain alkylene, which is optionally        substituted with from 1-2 independently selected R^(c); or    -   (ii) a bond that directly connects A in formula (I) to Z in        formula (I);

A is:

-   -   (i) CR^(A1)R^(A2), wherein each of R^(A1) and R^(A2) is        independently selected from hydrogen, halo, C₁-C₃ alkyl, or OR⁹;        or    -   (ii) C═O; or    -   (iii) C₃-C₅ cycloalkylene that is (a) substituted with 1 oxo;        and (b) optionally further substituted with from 1-4        independently selected R^(a); or    -   (iv) heterocycloalkylene containing from 3-5 ring atoms, wherein        from 1-2 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heterocycloalkylene        is (a) substituted with 1 oxo; and (b) is optionally further        substituted with from 1-4 independently selected R^(a);

Z is:

-   -   (i) —NR¹⁰R¹¹; or    -   (ii) —C(O)NR¹⁰R¹¹; or    -   (iii) —OR¹²; or    -   (iv) —S(O)_(n)R¹³, wherein n is 0, 1, or 2 or    -   (v) heterocycloalkenyl containing from 5-6 ring atoms, wherein        from 1-3 of the ring atoms is independently selected from N, NH,        N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S; and wherein said        heterocycloalkenyl is optionally substituted with from 1-4        independently selected R^(a);    -   (vi) C₆-C₁₀ aryl that is optionally substituted with from 1-4        independently selected R^(b); or    -   (vii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4 independently selected        R^(b); or    -   (viii) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (ix) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (x) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (xi) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

R⁹ is hydrogen; or C₁-C₃ alkyl that is optionally substituted withhydroxyl or C₁-C₃ alkoxy;

each of R¹⁰ and R¹¹ is independently selected from the substituentsdelineated collectively in (a) through (k) below:

-   -   (a) hydrogen;    -   (b) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b);    -   (c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6        of the ring atoms is independently selected from N, NH, N(C₁-C₃        alkyl), O, and S; and wherein said heteroaryl is optionally        substituted with from 1-4R^(b);    -   (d) C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is optionally        substituted with from 1-3R^(d);    -   (e) —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆ haloalkyl), or —C(O)O(C₁-C₆        alkyl);    -   (f) C₂-C₆ alkenyl or C₂-C₆ alkynyl;    -   (g) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   (h) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   (i) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   (j) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   (k) C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, each of which is        optionally substituted with from 1-4 independently selected        R^(a); and    -   (l) C₇-C₁₂ aralkyl, wherein the aryl portion is optionally the        aryl portion from is optionally substituted with from 1-4        independently selected R^(b),

R₁₂ is:

-   -   (i) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b); or    -   (ii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4R^(b); or    -   (iii) C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is        optionally substituted with from 1-3R^(d); or    -   (iv) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (v) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (vi) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (vii) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

R¹³ is:

-   -   (i) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b); or    -   (ii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4R^(b);    -   (iii) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (iv) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (v) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (vi) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

R^(a) at each occurrence is, independently selected from halo, hydroxyl,C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy,oxo, thioxo, ═NH, ═N(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, —NH₂,—NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and cyano;

R^(b) at each occurrence is independently selected from the substituentsdelineated in (aa) through (dd) below:

-   -   (aa) C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆        thiohaloalkoxy; C₁-C₆ alkyl, C₁-C₆ haloalkyl, —NH(C₁-C₆ alkyl),        N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), wherein the alkyl portion        of each is optionally substituted with from 1-3 independently        selected R^(e);    -   (bb) halo; hydroxyl; cyano; nitro; —NH₂; azido; sulfhydryl;        C₂-C₆ alkenyl; C₂-C₆ alkynyl; —C(O)H; —C(O)(C₁-C₆ alkyl);        —C(O)(C₁-C₆ haloalkyl); C(O)OH;    -   —C(O)O(C₁-C₆ alkyl); —C(O)NH₂; —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆        alkyl)₂; —SO₂(C₁-C₆ alkyl); —SO₂NH₂; —SO₂NH(C₁-C₆ alkyl);        —SO₂N(C₁-C₆ alkyl)₂;    -   (cc) C₃-C₆ cycloalkyl or heterocyclyl containing from 5-6 ring        atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is        independently selected from N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆        alkyl), O, and S; and wherein each of said phenyl and        heterocyclyl is optionally substituted with from 1-3        independently selected R^(a); and    -   (dd) phenyl or heteroaryl containing from 5-6 ring atoms,        wherein from 1-2 of the ring atoms of the heteroaryl is        independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;        wherein each of said phenyl and heteroaryl is optionally        substituted with from 1-3 substituents independently selected        from halo; hydroxyl; cyano; nitro; —NH₂; —NH(C₁-C₆ alkyl),        N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), C₁-C₆ alkoxy; C₁-C₆        haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆ thiohaloalkoxy; C₁-C₆ alkyl,        and C₁-C₆ haloalkyl;

R^(c) at each occurrence is, independently selected from halo, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano;

R^(d) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂₅—NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano; and

R^(e) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy; C₁-C₆ thioalkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thiohaloalkoxy; —NH₂;—NH(C₁-C₆ alkyl); N(C₁-C₆ alkyl)₂; —NHC(O)(C₁-C₆ alkyl); cyano; —C(O)H;—C(O)(C₁-C₆ alkyl); —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl);—C(O)NH₂; —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);—SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂; and L³-(C₁-C₆alkylene)-Cy, where in L³ is a —O—, —NH—, —NCH₃—, —C(O)—,

—C(O)NH—, —C(O)NCH₃—, —NHC(O)—, or —NCH₃C(O)—, and Cy is a saturated,partially unsaturated or aromatic carbocyclic or heterocyclic ringsystem;

or a salt (e.g., pharmaceutically acceptable salt) thereof.

In some embodiments, one or more of (A), (B), or (C) apply.

(A) Provided that when R and R′ are defined according to definition (3),then:

(i) each of L¹ and L² must be C₁-C₃ alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c) when A is CH₂; or

(ii) Z must be other than heteroaryl containing from 5-14 (e.g., 5-6 or6)ring atoms, wherein from 1-6 of the ring atoms is independentlyselected from N, NH, N(C₁-C₃ alkyl), O, and S; and wherein saidheteroaryl is optionally substituted with from 1-4 independentlyselected R^(b); e.g., other than substituted pyridyl, e.g., other thanpyridyl substituted with C₁-C₃ alkyl (e.g., CH₃), e.g., other than 2 or6-methylpyridyl.

(B) Each of R¹⁰ and R¹¹ cannot be optionally substituted naphthyl (e.g.,each of R¹⁰ and R¹¹ cannot be unsubstituted naphthyl). In embodiments,each of R¹⁰ and R¹¹ is other than optionally substituted naphthyl (e.g.,unsubstituted naphthyl) when R and R′ are defined according todefinitions (1), (2), and (4); and A is CR^(A1)R^(A2) (e.g., CHOR⁹,e.g., CHOH), and each of L¹ and L² is C₁-C₃ alkylene (e.g., each of L¹and L² is CH₂).

(C) R¹² and/or R¹³ cannot be substituted phenyl. In embodiments, R¹²and/or R¹³ cannot be substituted phenyl when R and R′ are definedaccording to definition (1); and A is CR^(A1)R^(A2) (e.g., CHOR⁹, e.g.,CHOH), and each of L¹ and L² is C₁-C₃ alkylene (e.g., each of L¹ and L²is CH₂).

In embodiments, (A), (B), or (C) applies. In other embodiments, (A) and(B); or (A) and (C); or (B) and (C) applies. In still other embodiments,(A), (B), and (C) apply.

In another aspect, methods for promoting post-natal mammalianneurogenesis in a subject in need thereof are featured. The methodsinclude administering to the subject an effective amount of a compoundhaving formula (I) or a pharmaceutically acceptable salt thereof, inwhich R and R′ together with C₂ and C₃, respectively, form a fusedphenyl ring having formula (II):

For purposes of clarification, it is understood that compounds in whichR and R′ together with C₂ and C₃, respectively, form a fused phenyl ringhaving formula (II) correspond to compounds having the following generalformula:

in which R¹, R², R³, R⁴, L¹, L², A, and Z can be as defined anywhereherein.

In embodiments, (A), (B), or (C) applies. In other embodiments, (A) and(B); or (A) and (C); or (B) and (C) applies. In still other embodiments,(A), (B), or (C) apply.

In another aspect, methods for promoting post-natal mammalianneurogenesis in a subject in need thereof are featured. The methodincludes administering to the subject an effective amount of a compoundhaving formula (I) or a pharmaceutically acceptable salt thereof, inwhich:

each of L¹ and L² is CH₂;

A is CR^(A1)R^(A2), wherein one of R^(A1) and R^(A2) is OR⁹, and theother is hydrogen;

Z is —NR¹⁰R¹¹; and

each of R¹⁰ and R¹¹ is independently selected from

(a) hydrogen;

(b) C₆-C₁₀ aryl that is optionally substituted with from 1-4R^(b);

(d) C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is optionallysubstituted with from 1-3R^(d);

(f) C₂-C₆ alkenyl or C₂-C₆ alkynyl.

In embodiments, (A), (B), or (C) applies. In other embodiments, (A) and(B); or (A) and (C); or (B) and (C) applies. In still other embodiments,(A), (B), and (C) apply.

In one aspect, compositions (e.g., a pharmaceutical composition) arefeatured, which includes a compound of formula (I) (and/or a compound ofany of the other formulae described herein) or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein anda pharmaceutically acceptable carrier. In some embodiments, thecompositions can include an effective amount of the compound or salt. Insome embodiments, the compositions can further include one or moreadditional therapeutic agents. These may include, but are not limitedto, antidepressant medications (including selective serotonin reuptakeinhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, andother antidepressant medications including but not limited tovenlafaxine, nefazadone, bupropion, mirtazapine, lithium and trazodone)and acetylcholinesterase inhibitors (including but not limited toAricept, Reminyl, and Exelon).

In another aspect, dosage forms are featured, which includes from about0.05 milligrams to about 2,000 milligrams (e.g., from about 0.1milligrams to about 1,000 milligrams, from about 0.1 milligrams to about500 milligrams, from about 0.1 milligrams to about 250 milligrams, fromabout 0.1 milligrams to about 100 milligrams, from about 0.1 milligramsto about 50 milligrams, or from about 0.1 milligrams to about 25milligrams) of a compound of formula (I) (and/or a compound of any ofthe other formulae described herein) or a salt (e.g., a pharmaceuticallyacceptable salt) thereof as defined anywhere herein. The dosage formscan further include a pharmaceutically acceptable carrier and/or anadditional therapeutic agent.

In one aspect, the compounds of formula (I) themselves (and/or acompound of any of the other formulae described herein) or a salt (e.g.,a pharmaceutically acceptable salt) thereof as defined anywhere hereinare featured. In another aspect, any of the formula (I) compoundsspecifically described herein are featured.

In one aspect, compounds having formula (I) are featured.

wherein:

each of R¹, R², R³, and R⁴ is independently selected from hydrogen,halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkynyl, cyclopropyl, —N₃, cyano,

—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), andnitro;

R and R′ are defined according to (1) or (2) below:

(1) R and R′ together with C₂ and C₃, respectively, form a fused phenylring having formula (II):

wherein each of R⁵, R⁶, R⁷, and R⁸ is independently selected fromhydrogen, halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy,C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₂-C₆ alkynyl, cyclopropyl, —N₃, cyano,

—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), andnitro; OR

(2) R and R′ together with C₂ and C₃, respectively, form a fused R andR′ together with C₂ and C₃, respectively, form a fused heteroaryl ringcontaining 6 ring atoms, wherein from 1-2 independently selected ringatoms is N; and wherein said heteroaryl ring is optionally substitutedwith from 1-2 independently selected R^(b);

each of L¹ and L² is, independently, C₁-C₃ alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c);

A is:

-   -   (i) CR^(A1)R^(A2), wherein each of R^(A1) and R^(A2) is        independently selected from hydrogen, halo, C₁-C₃ alkyl, and        OR⁹, wherein R⁹ is hydrogen or C₁-C₃ alkyl that is optionally        substituted with hydroxyl or C₁-C₃ alkoxy; or    -   (ii) C═O; or    -   (iii) C₃-C₅ cycloalkylene that is (a) substituted with 1 oxo;        and (b) optionally further substituted with from 1-4        independently selected R^(a); or    -   (iv) heterocycloalkylene containing from 3-5 ring atoms, wherein        from 1-2 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heterocycloalkylene        is (a) substituted with 1 oxo; and (b) is optionally further        substituted with from 1-4 independently selected R^(a);

Z is:

-   -   (i) —NR¹⁰R¹¹; or    -   (ii) —C(O)NR¹⁰R¹¹; or    -   (iii) —OR¹²; or    -   (iv) —S(O)_(n)R¹³, wherein n is 0, 1, or 2 or    -   (v) heterocycloalkenyl containing from 5-6 ring atoms, wherein        from 1-3 of the ring atoms is independently selected from N, NH,        N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S; and wherein said        heterocycloalkenyl is optionally substituted with from 1-4        independently selected R^(a);    -   (vi) C₆-C₁₀ aryl that is optionally substituted with from 1-4        independently selected R^(b); or    -   (vii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4 independently selected        R^(b); or    -   (viii) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (ix) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (x) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (xi) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

each of R¹⁰ and R¹¹ is independently selected from the substituentsdelineated collectively in (a) through (k) below:

-   -   (a) hydrogen;    -   (b) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b);    -   (c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6        of the ring atoms is independently selected from N, NH, N(C₁-C₃        alkyl), O, and S; and wherein said heteroaryl is optionally        substituted with from 1-4R^(b);    -   (d) C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is optionally        substituted with from 1-3R^(d);    -   (e) —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆ haloalkyl), or —C(O)O(C₁-C₆        alkyl);    -   (f) C₂-C₆ alkenyl or C₂-C₆ alkynyl;    -   (g) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   (h) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   (i) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   (j) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   (k) C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, each of which is        optionally substituted with from 1-4 independently selected        R^(a); and    -   (l) C₇-C₁₂ aralkyl, wherein the aryl portion is optionally the        aryl portion from is optionally substituted with from 1-4        independently selected R^(b),    -   provided that one of R¹⁰ and R¹¹ must be selected from (b), (c),        (g), (h), (i), (j), and (k);

R¹² is:

-   -   (i) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b); or    -   (ii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4R^(b); or    -   (iii) C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is        substituted with from 1-3R^(d);    -   (iv) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (v) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a); or    -   (vi) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a); or    -   (vii) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

R¹³ is:

-   -   (i) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b); or    -   (ii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4R^(b);    -   (iii) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (iv) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (v) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (vi) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

R^(a) at each occurrence is, independently selected from halo, hydroxyl,C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy,oxo, thioxo, ═NH, ═N(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, —NH₂,—NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and cyano;

R^(b) at each occurrence is independently selected from the substituentsdelineated in (aa) through (dd) below:

-   -   (aa) C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆        thiohaloalkoxy; —O—(CH₂)₁₋₃—[O(CH₂)₁₋₃]₁₋₃—H; —C₁-C₆ alkyl,        C₁-C₆ haloalkyl,    -   —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl),        wherein the alkyl portion of each is optionally substituted with        from 1-3 independently selected R^(e);    -   (bb) halo; hydroxyl; cyano; nitro; —NH₂; azido; sulfhydryl;        C₂-C₆ alkenyl; C₂-C₆ alkynyl; —C(O)H; —C(O)(C₁-C₆ alkyl);        —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl); —C(O)NH₂;        —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);        —SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂;    -   (cc) C₃-C₆ cycloalkyl or heterocyclyl containing from 5-6 ring        atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is        independently selected from N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆        alkyl), O, and S; and wherein each of said phenyl and        heterocyclyl is optionally substituted with from 1-3        independently selected R^(a); and    -   (dd) phenyl or heteroaryl containing from 5-6 ring atoms,        wherein from 1-2 of the ring atoms of the heteroaryl is        independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;        wherein each of said phenyl and heteroaryl is optionally        substituted with from 1-3 substituents independently selected        from halo; hydroxyl; cyano; nitro; —NH₂; —NH(C₁-C₆ alkyl),        N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), C₁-C₆ alkoxy; C₁-C₆        haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆ thiohaloalkoxy; C₁-C₆ alkyl,        and C₁-C₆ haloalkyl;

R^(c) at each occurrence is, independently selected from halo, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano;

R^(d) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano; and

R^(e) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy; C₁-C₆ thioalkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thiohaloalkoxy; —NH₂;—NH(C₁-C₆ alkyl); N(C₁-C₆ alkyl)₂; —NHC(O)(C₁-C₆ alkyl); cyano; —C(O)H;—C(O)(C₁-C₆ alkyl); —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl);—C(O)NH₂; —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);—SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂; and L³-(C₁-C₆alkylene)-biotin, where in L³ is a —O—, —NH—, —NCH₃—, —C(O)—,

—C(O)NH—, —C(O)NCH₃—, —NHC(O)—, or —NCH₃C(O)—;

or a pharmaceutically acceptable salt thereof.

In embodiments, 1, 2, 3, 4, 5, or 6 of the following can apply

-   -   provided that R³ and R⁶ cannot both be hydrogen when A is CH₂,        and R and R′ are defined according to definition (1);    -   provided that R³ cannot be hydrogen when A is CH₂, and R and R′        are defined according to definition (2);    -   provided that R³ and R⁶ cannot both be chloro when A is CH₂, R        and R′ are defined according to definition (1), Z is —OR¹², and        R¹² is unsubstituted phenyl;    -   provided that R³ and R⁶ cannot both be bromo when A is CH₂, R        and R′ are defined according to definition (1), Z is —OR′², and        R¹² is phenyl that is substituted with pyridyl or alkyl that is        substituted with from 1-3R^(e);    -   provided that R³ and R⁶ cannot both be hydrogen when A is        CH(CH₃), R and R′ are defined according to definition (1), Z is        NR¹⁰R¹¹, R¹⁰ is CH₃, and R¹¹ is unsubstituted phenyl;    -   provided that when A is CR^(A1)R^(A2), and one of R^(A1) and        R^(A2) is OH (i.e., R⁹ is H), then the other of R^(A1) and        R^(A2) is C₁-C₃ alkyl.

In another aspect, pharmaceutical compositions are featured that includethe above-described compounds (or salts thereof as described herein) anda pharmaceutically acceptable carrier. In embodiments, 1, 2, 3, 4, 5, or6 of the above described provisions can apply.

In one aspect, compounds having formula (I) are featured.

wherein:

each of R¹, R², R³, and R⁴ is independently selected from hydrogen,halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkynyl, cyclopropyl, —N₃, cyano, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and nitro;

R and R′ are defined according to (1) or (2) below:

(1) R and R′ together with C₂ and C₃, respectively, form a fused phenylring having formula (II):

wherein each of R⁵, R⁶, R⁷, and R⁸ is independently selected fromhydrogen, halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy,C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₂-C₆ alkynyl, cyclopropyl, —N₃, cyano, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and nitro; OR

(2) R and R′ together with C₂ and C₃, respectively, form a fused R andR′ together with C₂ and C₃, respectively, form a fused heteroaryl ringcontaining 6 ring atoms, wherein from 1-2 independently selected ringatoms is N; and wherein said heteroaryl ring is optionally substitutedwith from 1-2 independently selected R^(b);

each of L¹ and L² is, independently, C₁-C₃ alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c);

A is:

-   -   (i) CR^(A1)R^(A2), wherein each of R^(A1) and R^(A2) is        independently selected from hydrogen, halo, C₁-C₃ alkyl, and        OR⁹, wherein R⁹ is C₁-C₃ alkyl that is optionally substituted        with hydroxyl or C₁-C₃ alkoxy; or    -   (ii) C═O; or    -   (iii) C₃-C₅ cycloalkylene that is (a) substituted with 1 oxo;        and (b) optionally further substituted with from 1-4        independently selected R^(a); or    -   (iv) heterocycloalkylene containing from 3-5 ring atoms, wherein        from 1-2 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heterocycloalkylene        is (a) substituted with 1 oxo; and (b) is optionally further        substituted with from 1-4 independently selected R^(a);

Z is:

-   -   (i) —NR¹⁰R¹¹; or    -   (ii) —C(O)NR¹⁰R¹¹; or    -   (iii) —OR¹²; or    -   (iv) —S(O)_(n)R¹³, wherein n is 0, 1, or 2 or    -   (v) heterocycloalkenyl containing from 5-6 ring atoms, wherein        from 1-3 of the ring atoms is independently selected from N, NH,        N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S; and wherein said        heterocycloalkenyl is optionally substituted with from 1-4        independently selected R^(a);    -   (vi) C₆-C₁₀ aryl that is optionally substituted with from 1-4        independently selected R^(b); or    -   (vii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4 independently selected        R^(b); or    -   (viii) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (ix) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (x) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (xi) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

each of R¹⁰ and R¹¹ is independently selected from the substituentsdelineated collectively in (a) through (k) below:

-   -   (a) hydrogen;    -   (b) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b);    -   (c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6        of the ring atoms is independently selected from N, NH, N(C₁-C₃        alkyl), O, and S; and wherein said heteroaryl is optionally        substituted with from 1-4R^(b);    -   (d) C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is optionally        substituted with from 1-3R^(d);    -   (e) —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆ haloalkyl), or —C(O)O(C₁-C₆        alkyl);    -   (f) C₂-C₆ alkenyl or C₂-C₆ alkynyl;    -   (g) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   (h) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   (i) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   (j) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   (k) C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, each of which is        optionally substituted with from 1-4 independently selected        R^(a); and    -   (l) C₇-C₁₂ aralkyl, wherein the aryl portion is optionally the        aryl portion from is optionally substituted with from 1-4        independently selected R^(b),    -   provided that one of R¹⁰ and R¹¹ must be selected from (b), (c),        (g), (h), (i), (j), and (k);

R¹² is:

-   -   (i) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b); or    -   (ii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4R^(b); or    -   (iii) C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is        substituted with from 1-3R^(d);    -   (iv) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (v) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (vi) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and    -   (2) from 1-2 of the ring atoms of the heterocyclyl portion is        independently selected from N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆        alkyl), O, and S; and wherein said heterocyclyl portion is        optionally substituted with from 1-3 independently selected        R^(a);    -   or    -   (vii) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

R¹³ is:

-   -   (i) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b); or    -   (ii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4R^(b);    -   (iii) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (iv) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (v) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (vi) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

R^(a) at each occurrence is, independently selected from halo, hydroxyl,C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy,oxo, thioxo, ═NH, ═N(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, —NH₂,—NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and cyano;

R^(b) at each occurrence is independently selected from the substituentsdelineated in (aa) through (dd) below:

-   -   (aa) C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆        thiohaloalkoxy; —O—(CH₂)₁₋₃—[O(CH₂)₁₋₃]₁₋₃—H; —C₁-C₆ alkyl,        C₁-C₆ haloalkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,        —NHC(O)(C₁-C₆ alkyl), wherein the alkyl portion of each is        optionally substituted with from 1-3 independently selected        R^(e);    -   (bb) halo; hydroxyl; cyano; nitro; —NH₂; azido; sulfhydryl;        C₂-C₆ alkenyl; C₂-C₆ alkynyl; —C(O)H; —C(O)(C₁-C₆ alkyl);        —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl); —C(O)NH₂;        —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);        —SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂;    -   (cc) C₃-C₆ cycloalkyl or heterocyclyl containing from 5-6 ring        atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is        independently selected from N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆        alkyl), O, and S; and wherein each of said phenyl and        heterocyclyl is optionally substituted with from 1-3        independently selected R^(a); and    -   (dd) phenyl or heteroaryl containing from 5-6 ring atoms,        wherein from 1-2 of the ring atoms of the heteroaryl is        independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;        wherein each of said phenyl and heteroaryl is optionally        substituted with from 1-3 substituents independently selected        from halo; hydroxyl; cyano; nitro; —NH₂; —NH(C₁-C₆ alkyl),        N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), C₁-C₆ alkoxy; C₁-C₆        haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆ thiohaloalkoxy; C₁-C₆ alkyl,        and C₁-C₆ haloalkyl;

R^(c) at each occurrence is, independently selected from halo, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano;

R^(d) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano; and

R^(e) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy; C₁-C₆ thioalkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thiohaloalkoxy; —NH₂;—NH(C₁-C₆ alkyl); N(C₁-C₆ alkyl)₂; —NHC(O)(C₁-C₆ alkyl); cyano; —C(O)H;—C(O)(C₁-C₆ alkyl); —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl);—C(O)NH₂; —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);—SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂; and L³-(C₁-C₆alkylene)-biotin, where in L³ is a —O—, —NH—, —NCH₃—, —C(O)—, —C(O)NH—,—C(O)NCH₃—, —NHC(O)—, or —NCH₃C(O)—;

or a pharmaceutically acceptable salt thereof.

In embodiments, 1, 2, 3, 4, or 5 of the following can apply

-   -   provided that R³ and R⁶ cannot both be hydrogen when A is CH₂,        and R and R′ are defined according to definition (1);    -   provided that R³ cannot be hydrogen when A is CH₂, and R and R′        are defined according to definition (2);    -   provided that R³ and R⁶ cannot both be chloro when A is CH₂, R        and R′ are defined according to definition (1), Z is —OR′², and        R′² is unsubstituted phenyl;    -   provided that R³ and R⁶ cannot both be bromo when A is CH₂, R        and R′ are defined according to definition (1), Z is —OR′², and        R′² is phenyl that is substituted with pyridyl or alkyl that is        substituted with from 1-3R^(e); and    -   provided that R³ and R⁶ cannot both be hydrogen when A is        CH(CH₃), R and R′ are defined according to definition (1), Z is        NR¹⁰R¹¹, R¹⁰ is CH₃, and R¹¹ is unsubstituted phenyl.

In another aspect, pharmaceutical compositions are featured that includethe above-described compounds (or salts thereof as described herein) anda pharmaceutically acceptable carrier. In embodiments, 1, 2, 3, 4, or 5of the above described provisions can apply.

In another aspect, compounds having formula (I) are featured

wherein:

each of R¹, R², R³, and R⁴ is independently selected from hydrogen,halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkynyl, cyclopropyl, —N₃, cyano,

—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), andnitro;

R and R′ are defined according to (1) or (2) below:

(1) R and R′ together with C₂ and C₃, respectively, form a fused phenylring having formula (II):

wherein each of R⁵, R⁶, R⁷, and R⁸ is independently selected fromhydrogen, halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy,C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₂-C₆ alkynyl, cyclopropyl, —N₃, cyano,

—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), andnitro; OR

(2) R and R′ together with C₂ and C₃, respectively, form a fused R andR′ together with C₂ and C₃, respectively, form a fused heteroaryl ringcontaining 6 ring atoms, wherein from 1-2 independently selected ringatoms is N; and wherein said heteroaryl ring is optionally substitutedwith from 1-2 independently selected R^(b);

each of L¹ and L² is, independently, C₁-C₃ alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c);

A is CR^(A1)R^(A2), wherein one of R^(A1) and R^(A2) is —OH, and theother of R^(A1) and R^(A2) is hydrogen or C₁-C₃ alkyl;

Z is —OR¹² or —S(O)^(n)R¹³, wherein n is 0, 1, or 2;

each of R¹² and R¹³ is:

-   -   (i) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b); or    -   (ii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4R^(b);    -   (iii) C₁-C₆ alkyl or C₁-C₆ haloalkyl (e.g., C₁-C₆ alkyl), each        of which is substituted with from 1-3R^(d) or    -   (iv) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   or    -   (v) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (vi) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   or    -   (vii) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);

R^(a) at each occurrence is, independently selected from halo, hydroxyl,C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy,oxo, thioxo, ═NH, ═N(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, —NH₂,—NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and cyano;

R^(b) at each occurrence is independently selected from the substituentsdelineated in (aa) through (dd) below:

-   -   (aa) C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆        thiohaloalkoxy; —O—(CH₂)₁₋₃—[O(CH₂)₁₋₃]₁₋₃—H; —C₁-C₆ alkyl,        C₁-C₆ haloalkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,        —NHC(O)(C₁-C₆ alkyl), wherein the alkyl portion of each is        optionally substituted with from 1-3 independently selected        R^(e);    -   (bb) halo; hydroxyl; cyano; nitro; —NH₂; azido; sulfhydryl;        C₂-C₆ alkenyl; C₂-C₆ alkynyl; —C(O)H; —C(O)(C₁-C₆ alkyl);        —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl); —C(O)NH₂;        —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);        —SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂;    -   (cc) C₃-C₆ cycloalkyl or heterocyclyl containing from 5-6 ring        atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is        independently selected from N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆        alkyl), O, and S; and wherein each of said phenyl and        heterocyclyl is optionally substituted with from 1-3        independently selected R^(a); and    -   (dd) phenyl or heteroaryl containing from 5-6 ring atoms,        wherein from 1-2 of the ring atoms of the heteroaryl is        independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;        wherein each of said phenyl and heteroaryl is optionally        substituted with from 1-3 substituents independently selected        from halo; hydroxyl; cyano; nitro; —NH₂; —NH(C₁-C₆ alkyl),        N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), C₁-C₆ alkoxy; C₁-C₆        haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆ thiohaloalkoxy; C₁-C₆ alkyl,        and C₁-C₆ haloalkyl;

R^(c) at each occurrence is, independently selected from halo, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano;

R^(d) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano; and

R^(e) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy; C₁-C₆ thioalkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thiohaloalkoxy; —NH₂;—NH(C₁-C₆ alkyl); N(C₁-C₆ alkyl)₂; —NHC(O)(C₁-C₆ alkyl); cyano; —C(O)H;—C(O)(C₁-C₆ alkyl); —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl);—C(O)NH₂; —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);—SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂; and L³-(C₁-C₆alkylene)-biotin, where in L³ is a —O—, —NH—, —NCH₃—, —C(O)—, —C(O)NH—,—C(O)NCH₃—, —NHC(O)—, or —NCH₃C(O)—;

or a pharmaceutically acceptable salt thereof.

In embodiments, 1, 2, 3, or 4 of the following can apply:

-   -   provided that R³ and R⁶ cannot both be hydrogen when R and R′        are defined according to definition (1);    -   provided that R³ and R⁶ cannot both be chloro when R and R′ are        defined according to definition (1), Z is —OR¹², and R¹² is        phenyl substituted with chloro, formyl, or —NHC(O)CH₃;    -   provided that R³ and R⁶ cannot both be bromo when R and R′ are        defined according to definition (1), Z is —OR¹², and R¹² is        phenyl substituted with —NHC(O)CH₃; and    -   provided that R³ and R⁶ cannot both be bromo when R and R′ are        defined according to definition (1), Z is —SR¹³, and R¹³ is        phenyl substituted with —OH.

In another aspect, pharmaceutical compositions are featured that includethe above-described compounds (or salts thereof as described herein) anda pharmaceutically acceptable carrier. In embodiments, 1, 2, 3, 4, or 5of the above described provisions can apply.

In another aspect, compounds having formula (I) are featured:

wherein:

each of R¹, R², R³, and R⁴ is independently selected from hydrogen,halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkynyl, cyclopropyl, —N₃, cyano, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and nitro;

R and R′ together with C₂ and C₃, respectively, form a fusedheterocyclic ring containing from 5-6 ring atoms, wherein from 1-2 ofthe ring atoms is independently selected from N, NH, N(C₁-C₆ alkyl),NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclic ring isoptionally substituted with from 1-3 independently selected R^(a);

each of L¹ and L² is, independently, C₁-C₃ alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c);

A is:

-   -   (i) CR^(A1)R^(A2), wherein one of R^(A1) and R^(A2) is        independently selected from hydrogen, halo, C₁-C₃ alkyl, and        OR⁹; and the other of R^(A1) and R^(A2) is independently        selected from halo, C₁-C₃ alkyl, and OR⁹; wherein R⁹ is hydrogen        or C₁-C₃ alkyl that is optionally substituted with hydroxyl or        C₁-C₃ alkoxy; or    -   (ii) C═O;

Z is:

-   -   (i) —NR¹⁰R¹¹; or    -   (ii) —C(O)NR¹⁰R¹¹; or    -   (iii) —OR¹²; or    -   (iv) —S(O)_(n)R¹³, wherein n is 0, 1, or 2 or    -   (vi) C₆-C₁₀ aryl that is optionally substituted with from 1-4        independently selected R^(b); or    -   (vii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4 independently selected        R^(b); or

each of R¹⁰ and R¹¹ is independently selected from the substituentsdelineated collectively in (a) through (k) below:

-   -   (a) hydrogen;    -   (b) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b);    -   (c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6        of the ring atoms is independently selected from N, NH, N(C₁-C₃        alkyl), O, and S; and wherein said heteroaryl is optionally        substituted with from 1-4R^(b);    -   (d) C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is optionally        substituted with from 1-3R^(d);    -   (e) —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆ haloalkyl), or —C(O)O(C₁-C₆        alkyl);    -   (f) C₂-C₆ alkenyl or C₂-C₆ alkynyl; and    -   (l) C₇-C₁₂ aralkyl, wherein the aryl portion is optionally the        aryl portion from is optionally substituted with from 1-4        independently selected R^(b),    -   provided that one of R¹⁰ and R¹¹ must be selected from (b) and        (c);

R¹² is:

-   -   (i) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b); or    -   (ii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4R^(b);

R¹³ is:

-   -   (i) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b); or    -   (ii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4R^(b);

R^(a) at each occurrence is, independently selected from halo, hydroxyl,C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy,oxo, thioxo, ═NH, ═N(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, —NH₂,—NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and cyano;

R^(b) at each occurrence is independently selected from the substituentsdelineated in (aa) through (dd) below:

-   -   (aa) C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆        thiohaloalkoxy; —O—(CH₂)₁₋₃—[O(CH₂)₁₋₃]₁₋₃—H; —C₁-C₆ alkyl,        C₁-C₆ haloalkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,        —NHC(O)(C₁-C₆ alkyl), wherein the alkyl portion of each is        optionally substituted with from 1-3 independently selected        R^(e);    -   (bb) halo; hydroxyl; cyano; nitro; —NH₂; azido; sulfhydryl;        C₂-C₆ alkenyl; C₂-C₆ alkynyl; —C(O)H; —C(O)(C₁-C₆ alkyl);        —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl); —C(O)NH₂;        —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);        —SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂;    -   (cc) C₃-C₆ cycloalkyl or heterocyclyl containing from 5-6 ring        atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is        independently selected from N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆        alkyl), O, and S; and wherein each of said phenyl and        heterocyclyl is optionally substituted with from 1-3        independently selected R^(a); and    -   (dd) phenyl or heteroaryl containing from 5-6 ring atoms,        wherein from 1-2 of the ring atoms of the heteroaryl is        independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;        wherein each of said phenyl and heteroaryl is optionally        substituted with from 1-3 substituents independently selected        from halo; hydroxyl; cyano; nitro; —NH₂; —NH(C₁-C₆ alkyl),        N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), C₁-C₆ alkoxy; C₁-C₆        haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆ thiohaloalkoxy; C₁-C₆ alkyl,        and C₁-C₆ haloalkyl;

R^(c) at each occurrence is, independently selected from halo, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano;

R^(d) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano; and

R^(e) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy; C₁-C₆ thioalkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thiohaloalkoxy; —NH₂;—NH(C₁-C₆ alkyl); N(C₁-C₆ alkyl)₂; —NHC(O)(C₁-C₆ alkyl); cyano; —C(O)H;—C(O)(C₁-C₆ alkyl); —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl);—C(O)NH₂; —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);—SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂; and L³-(C₁-C₆alkylene)-biotin, where in L³ is a —O—, —NH—, —NCH₃—, —C(O)—,

—C(O)NH—, —C(O)NCH₃—, —NHC(O)—, or —NCH₃C(O)—;

or a pharmaceutically acceptable salt thereof.

In embodiments, provision (A) described herein can apply.

In another aspect, compounds having formula (I) are featured:

wherein:

each of R¹, R², R³, and R⁴ is independently selected from hydrogen,halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkynyl, cyclopropyl, —N₃, cyano,

—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), andnitro;

each of R and R′ is, independently, hydrogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl;

each of L¹ and L² is, independently, C₁-C₃ alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c);

A is:

-   -   (i) CR^(A1)R^(A2), wherein one of R^(A1) and R^(A2) is        independently selected from hydrogen, fluoro, chloro, C₁-C₃        alkyl, and OR⁹; and the other of R^(A1) and R^(A2) is        independently selected from fluoro, chloro, C₁-C₃ alkyl, and        OR⁹; wherein R⁹ is hydrogen or C₁-C₃ alkyl that is optionally        substituted with hydroxyl or C₁-C₃ alkoxy; or    -   (ii) C═O;

Z is:

-   -   (i) —NR¹⁰R¹¹; or    -   (ii) —C(O)NR¹⁰R¹¹; or    -   (iii) —OR¹²; or    -   (iv) —S(O)_(n)R¹³, wherein n is 0, 1, or 2 or    -   (vi) C₆-C₁₀ aryl that is optionally substituted with from 1-4        independently selected R^(b); or    -   (vii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4 independently selected        R^(b); or

each of R¹⁰ and R¹¹ is independently selected from the substituentsdelineated collectively in (a) through (k) below:

-   -   (a) hydrogen;    -   (b) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b);    -   (c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6        of the ring atoms is independently selected from N, NH, N(C₁-C₃        alkyl), O, and S; and wherein said heteroaryl is optionally        substituted with from 1-4R^(b);    -   (d) C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is optionally        substituted with from 1-3R^(d);    -   (e) —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆ haloalkyl), or —C(O)O(C₁-C₆        alkyl);    -   (f) C₂-C₆ alkenyl or C₂-C₆ alkynyl; and    -   (l) C₇-C₁₂ aralkyl, wherein the aryl portion is optionally the        aryl portion from is optionally substituted with from 1-4        independently selected R^(b),    -   provided that one of R¹⁰ and R¹¹ must be selected from (b) and        (c);

each of R¹² and R¹³ is:

-   -   (i) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b); or    -   (ii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4R^(b);

R^(a) at each occurrence is, independently selected from halo, hydroxyl,C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy,oxo, thioxo, ═NH, ═N(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, —NH₂,—NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and cyano;

R^(b) at each occurrence is independently selected from the substituentsdelineated in (aa) through (dd) below:

-   -   (aa) C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆        thiohaloalkoxy; —O—(CH₂)₁₋₃—[O(CH₂)₁₋₃]₁₋₃H; —C₁-C₆ alkyl, C₁-C₆        haloalkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆        alkyl), wherein the alkyl portion of each is optionally        substituted with from 1-3 independently selected R^(e);    -   (bb) halo; hydroxyl; cyano; nitro; —NH₂; azido; sulfhydryl;        C₂-C₆ alkenyl; C₂-C₆ alkynyl; —C(O)H; —C(O)(C₁-C₆ alkyl);        —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl); —C(O)NH₂;        —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);        —SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂;    -   (cc) C₃-C₆ cycloalkyl or heterocyclyl containing from 5-6 ring        atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is        independently selected from N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆        alkyl), O, and S; and wherein each of said phenyl and        heterocyclyl is optionally substituted with from 1-3        independently selected R^(a); and    -   (dd) phenyl or heteroaryl containing from 5-6 ring atoms,        wherein from 1-2 of the ring atoms of the heteroaryl is        independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;        wherein each of said phenyl and heteroaryl is optionally        substituted with from 1-3 substituents independently selected        from halo; hydroxyl; cyano; nitro; —NH₂; —NH(C₁-C₆ alkyl),        N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), C₁-C₆ alkoxy; C₁-C₆        haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆ thiohaloalkoxy; C₁-C₆ alkyl,        and C₁-C₆ haloalkyl;

R^(c) at each occurrence is, independently selected from halo, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano;

R^(d) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and cyano; and

R^(e) at each occurrence is, independently selected from hydroxyl, C₁-C₆alkoxy; C₁-C₆ thioalkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thiohaloalkoxy; —NH₂;—NH(C₁-C₆ alkyl); N(C₁-C₆ alkyl)₂; —NHC(O)(C₁-C₆ alkyl); cyano; —C(O)H;—C(O)(C₁-C₆ alkyl); —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl);—C(O)NH₂; —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl);—SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂; and L³-(C₁-C₆alkylene)-biotin, where in L³ is a —O—, —NH—, —NCH₃—, —C(O)—, —C(O)NH—,—C(O)NCH₃—, —NHC(O)—, or —NCH₃C(O)—;

or a pharmaceutically acceptable salt thereof.

In one aspect, compounds of formula (III) are featured in which:

A is CR^(A1)R^(A2), in which each of R^(A1) and R^(A2) is,independently, hydrogen, halo, or C₁-C₃ alkyl; or

A is CR^(A1)R^(A2), in which one of R^(A1) and R^(A2) is halo (e.g.,fluoro), and the other of R^(A1) and R^(A2) is, independently, hydrogen,halo, or C₁-C₃ alkyl (e.g., hydrogen); or

A is CR^(A1)R^(A2), in which one of R^(A1) and R^(A2) is halo (e.g.,fluoro), and the other of R^(A1) and R^(A2) is hydrogen; and

R¹, R², R³, R⁴, L¹, L², and Z can be as defined anywhere herein; or asalt (e.g., pharmaceutically acceptable salt) thereof.

In embodiments, (B) and/or (C) applies.

In one aspect, compounds of formula (III) are featured in which:

one of R^(A1) and R^(A2) can be OR⁹. In embodiments, the other of R^(A1)and R^(A2) can be as defined anywhere herein; e.g., the other of R^(A1)and R^(A2) can be hydrogen or C₁-C₃ alkyl. For example, one of R^(A1)and R^(A2) can be OR⁹, and the other of R^(A1) and R^(A2) is hydrogen orC₁-C₃ alkyl. In embodiments, R⁹ can be hydrogen or C₁-C₃ alkyl; and

R¹, R², R³, R⁴, L¹, L², and Z can be as defined anywhere herein; or asalt (e.g., pharmaceutically acceptable salt) thereof.

In embodiments, one or more of the following apply, e.g., when A is CHOHand Z is NR¹⁰R¹¹:

-   -   each of R³ and R⁶ is CH₃; and/or each of R³ and R⁶ is bromo;        and/or each of R³ and R⁶ is chloro; and/or one of R³ and R⁶ is        CH₃ (e.g., R⁶), and the other is bromo (e.g., R³);    -   each of R¹⁰ and R¹¹ is other than hydrogen;    -   each of R¹⁰ and R¹¹ is hydrogen;    -   one of R¹⁰ and R¹¹ is heteroaryl as defined anywhere herein;    -   L¹ and/or L² is C₂-C₃ alkylene (optionally substituted);    -   (B) and/or (C) applies.

In one aspect, compounds of formula (III) are featured in which Z isother than NR¹⁰R¹¹; and R¹, R², R³, R⁴, L¹, L², Z, and A can be asdefined anywhere herein; or a salt (e.g., pharmaceutically acceptablesalt) thereof. In embodiments, (B) and/or (C) applies.

In one aspect, compounds of formula (III) are featured in which Z is−OR¹² and/or —S(O)_(n)R¹³; and R¹, R², R³, R⁴, L¹, L², and A can be asdefined anywhere herein; or a salt (e.g., pharmaceutically acceptablesalt) thereof. In embodiments, (B) and/or (C) applies.

In one aspect, compounds of formula (III) are featured in which A is(ii) C═O; and/or (iv) heterocycloalkylene containing from 3-5 ringatoms, wherein from 1-2 of the ring atoms is independently selected fromN, NH, N(C₁-C₃ alkyl), O, and S; and wherein said heterocycloalkylene is(a) substituted with 1 oxo; and (b) is optionally further substitutedwith from 1-4 independently selected R^(a); and R¹, R², R³, R⁴, L¹, L²,and Z can be as defined anywhere herein; or a salt (e.g.,pharmaceutically acceptable salt) thereof.

Any of the aforementioned compounds can be used in any of the methods orcompositions described anywhere herein.

This invention relates generally to stimulating neurogenesis (e.g.,post-natal neurogenesis, e.g., post-natal hippocampal neurogenesis) andprotecting neurons from death with a compound of formula (I) (and/or acompound of any of the other formulae described herein) or a salt (e.g.,a pharmaceutically acceptable salt) thereof as defined anywhere herein.

For example, methods of promoting the generation of neurons arefeatured. As another example, methods of promoting the survival, growth,development and/or function of neurons, particularly CNS, brain,cerebral, and hippocampal neurons are featured. As a further example,methods of stimulating post-natal hippocampal neurogenesis are featured.

In some embodiments, such methods can include in vitro methods, e.g.,contacting a sample (e.g., a cell or tissue) with a compound of formula(I) (and/or a compound of any of the other formulae described herein) ora salt (e.g., a pharmaceutically acceptable salt) thereof as definedanywhere herein. In other embodiments, the methods can includeadministering a compound of formula (I) (and/or a compound of any of theother formulae described herein) or a salt (e.g., a pharmaceuticallyacceptable salt) thereof as defined anywhere herein to a subject (e.g.,a mammal, such as a human).

Accordingly, in yet another aspect, this invention includes and featuresmethods of screening for (thereby identifying) compounds that stimulateneurogenesis (e.g., post-natal neurogenesis, e.g., post-natalhippocampal neurogenesis) or protect newborn neurons from cell death.E.g., such as those described in the Examples section.

In one aspect, methods for treating (e.g., controlling, relieving,ameliorating, alleviating, or slowing the progression of) or methods forpreventing (e.g., delaying the onset of or reducing the risk ofdeveloping) one or more diseases, disorders, or conditions caused by, orassociated with insufficient (e.g., aberrant) neurogenesis or unwantedneuronal cell death in a subject in need thereof are featured. Themethods include administering to the subject an effective amount of acompound a compound of formula (I) (and/or a compound of any of theother formulae described herein) or a salt (e.g., a pharmaceuticallyacceptable salt) thereof as defined anywhere herein to the subject.

In another aspect, the use of a compound of formula (I) (and/or acompound of any of the other formulae described herein) or a salt (e.g.,a pharmaceutically acceptable salt) thereof as defined anywhere hereinin the preparation of, or for use as, a medicament for the treatment(e.g., controlling, relieving, ameliorating, alleviating, or slowing theprogression of) or prevention (e.g., delaying the onset of or reducingthe risk of developing) of one or more diseases, disorders, orconditions caused by, or associated with, insufficient (e.g., aberrant)neurogenesis or unwanted neuronal cell death is featured.

In embodiments, the one or more diseases, disorders, or conditions caninclude neuropathies, nerve trauma, and neurodegenerative diseases. Inembodiments, the one or more diseases, disorders, or conditions can bediseases, disorders, or conditions caused by, or associated withinsufficient neurogenesis (e.g., aberrant hippocampal neurogenesis) asis believed to occur in neuropsychiatric diseases, or aberrant neuronalcell death as is believed to occur in neurodegenerative diseases.Examples of the one or more diseases, disorders, or conditions include,but are not limited to, schizophrenia, major depression, bipolardisorder, normal aging, epilepsy, traumatic brain injury, post-traumaticstress disorder, Parkinson's disease, Alzheimer's disease, Downsyndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis,Huntington's disease, stroke, radiation therapy, chronic stress, andabuse of neuro-active drugs, such as alcohol, opiates, methamphetamine,phencyclidine, and cocaine.

In some embodiments, the subject can be a subject in need thereof (e.g.,a subject identified as being in need of such treatment, such as asubject having, or at risk of having, one or more of the diseases orconditions described herein). Identifying a subject in need of suchtreatment can be in the judgment of a subject or a health careprofessional and can be subjective (e.g. opinion) or objective (e.g.measurable by a test or diagnostic method). In some embodiments, thesubject can be a mammal. In certain embodiments, the subject can be ahuman.

In another aspect, methods of making the compounds described herein arefeatured. In embodiments, the methods include taking any one of theintermediate compounds described herein and reacting it with one or morechemical reagents in one or more steps to produce a compound of formula(I) (and/or a compound of any of the other formulae described herein) ora salt (e.g., a pharmaceutically acceptable salt) thereof as definedanywhere herein.

In some embodiments, compounds in which A is CHOH, and each of L¹ and L²is C₁-C₃ alkylene (e.g., each of L¹ and L² is CH₂) can be converted tocompounds in which A is C(O), and each of L¹ and L² is C₁-C₃ alkylene(e.g., each of L¹ and L² is CH₂) that is substituted with C₁-C₆thioalkoxy (e.g., —SCH₃). The methods include contacting the startingmaterial with an oxidizing agent sulfur trioxide pyridine complex (see,e.g., Example 7a and 7b).

In one aspect, methods of making the pharmaceutical compositionsdescribed herein are featured. In embodiments, the methods includetaking any one or more of the compounds of formula (I) (and/or compoundsof any of the other formulae described herein) or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein,and mixing said compound(s) with one or more pharmaceutically acceptablecarriers.

In one aspect, kits for the treatment (e.g., controlling, relieving,ameliorating, alleviating, or slowing the progression of) or prevention(e.g., delaying the onset of or reducing the risk of developing) of oneor more diseases, disorders, or conditions caused by, or associated withinsufficient (e.g., aberrant) neurogenesis or unwanted neuronal celldeath are featured. The kits include (i) a compound of formula (I)(and/or compounds of any of the other formulae described herein) or asalt (e.g., a pharmaceutically acceptable salt) thereof as definedanywhere herein; and (ii) instructions that include a direction toadminister said compound to a subject (e.g., a patient).

Embodiments can include, for example, any one or more of the followingfeatures.

R³ is selected from halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₂-C₆ alkynyl, cyclopropyl, —N₃, cyano, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and nitro. Inembodiments, R³ is halo (e.g., bromo). In embodiments, each of R¹, R²,and R⁴ is hydrogen.

R and R′ together with C₂ and C₃, respectively, form a fused phenyl ringhaving formula (II):

R⁶ is selected from halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₂-C₆ alkynyl, cyclopropyl, —N₃, cyano, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and nitro. Inembodiments, R⁶ is halo (e.g., bromo) or C₁-C₆ alkyl (e.g., CH₃). Inembodiments, R⁶ is halo (e.g., bromo). In embodiments, each of R⁵, R⁷,and R⁸ is hydrogen.

In embodiments, each of R³ and R⁶ is an independently selectedsubstituent that is other than hydrogen. In certain embodiments, each ofR³ and R⁶ is independently selected from halo, hydroxyl, sulfhydryl,C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, cyclopropyl, —N₃, cyano,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), andnitro. For example, R³ can be halo (e.g., bromo); and R⁶ can be halo(e.g., bromo) or C₁-C₆ alkyl (e.g., CH₃); e.g., halo (e.g., bromo). Inembodiments, each of R¹, R², and R⁴ is hydrogen; and each of R⁵, R⁷, andR⁸ is hydrogen.

In embodiments, R and R′ together with C₂ and C₃, respectively, form afused heteroaryl ring containing from 5-6 ring atoms, wherein from 1-2of the ring atoms is independently selected from N, NH, N(C₁-C₃ alkyl),O, and S; and wherein said heteroaryl ring is optionally substitutedwith from 1-3 independently selected R^(b).

For example, R and R′ together with C₂ and C₃, respectively, form afused heteroaryl ring containing −6 ring atoms, wherein from 1-2independently selected ring atoms is N; and wherein said heteroaryl ringis optionally substituted with from 1-2 independently selected R^(b).

In embodiments, R and R′ together with C₂ and C₃, respectively, form afused heterocyclic ring containing from 5-6 ring atoms, wherein from 1-2of the ring atoms is independently selected from N, NH, N(C₁-C₆ alkyl),NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclic ring isoptionally substituted with from 1-3 independently selected R^(a).

For example, R and R′ together with C₂ and C₃, respectively, form afused heterocyclic ring containing 6 ring atoms, wherein from 1-2 of thering atoms is independently selected from N, NH, N(C₁-C₆ alkyl), andNC(O)(C₁-C₆ alkyl); and wherein said heterocyclic ring is optionallysubstituted with from 1-3 independently selected R^(a).

In embodiments, R and R′ is, independently, hydrogen, C₁-C₆ alkyl, orC₁-C₆ haloalkyl (e.g., C₁-C₆ alkyl, or C₁-C₆ haloalkyl; e.g., C₁-C₆alkyl).

Each of L¹ and L² is, independently, C₁-C₃ straight chain alkylene,which is optionally substituted with from 1-2 independently selectedR^(c). For example, each of L¹ and L² is CH₂.

A is CR^(A1)R^(A2), in which each of R^(A1) and R^(A2) is,independently, hydrogen, halo, C₁-C₃ alkyl, or OR⁹.

In some embodiments, A is other than CH₂.

In embodiments, one of R^(A1) and R^(A2) can be independently selectedfrom hydrogen, halo, C₁-C₃ alkyl, and OR⁹; and the other of R^(A1) andR^(A2) can be independently selected from halo, C₁-C₃ alkyl, and OR⁹.For example, one of R^(A1) and R^(A2) is halo, C₁-C₃ alkyl, or OR⁹(e.g., halo or OR⁹); and the other is hydrogen or C1-C3 alkyl.

In embodiments, one of R^(A1) and R^(A2) is halo, and the other ofR^(A1) and R^(A2) is hydrogen or halo. For example, one of R^(A1) andR^(A2) is fluoro, and the other of R^(A1) and R^(A2) is hydrogen orfluoro. In either embodiments, one of R^(A1) and R^(A2) is OR⁹; and theother of R^(A1) and R^(A2) is C₁-C₃ alkyl. For example, one of R^(A1)and R^(A2) is OH; and the other of R^(A1) and R^(A2) is CH₃.

In embodiments, the carbon attached to R^(A1) and R^(A2) is substitutedwith four different substituents (for purposes of clarification, thesefour substituents include R^(A1) and R^(A2)) and is therefore astereogenic center.

In certain embodiments, the carbon attached to R^(A1) and R^(A2) is (R)configured, meaning that the carbon attached to R^(A1) and R^(A2) hasthe (R) configuration (Cahn Ingold Prelog sequence rules notation). Suchcompounds are sometimes referred to herein as an “(R)-configuredcompound” (this term also includes compounds that further contain one ormore stereogenic centers in addition to the (R) —CR^(A1)R^(A2)stereogenic center).

In other embodiments, the carbon attached to R^(A1) and R^(A2) is (S)configured, meaning that the carbon attached to R^(A1) and R^(A2) hasthe (S) configuration (Cahn Ingold Prelog sequence rules notation). Suchcompounds are sometimes referred to herein as an “(S)-configuredcompound” (this term also includes compounds that further contain one ormore stereogenic centers in addition to the (S)—CR^(A1)R^(A2)stereogenic center).

In embodiments, the (R) configured compound (or salt, e.g., apharmaceutically acceptable salt, thereof) is substantially free of(e.g., contains less than about 5% of, less than about 2% of, less thanabout 1%, less than about 0.5% of) a formula (I) compound (or saltthereof as described herein) that is (S) configured at the carbonattached to R^(A1) and R^(A2) (i.e., a formula (I) compound in which thecarbon attached to R^(A1) and R^(A2) has the (S) configuration). Forexample, the (R) configured compound can be an (R)-enantiomer that issubstantially free of its opposing (S) enantiomer. As another example,an (R) configured compound can be substantially free of a diastereomerin which the carbon attached to R^(A1) and R^(A2) has the (S)configuration. In certain embodiments, the (R) configured compound canbe additionally in substantially pure form (e.g., contains less thanabout 5% of, less than about 2% of, less than about 1%, less than about0.5% of other substances, including, for example, one or more of otherformula (I) compounds, non-formula (I) compounds, or biological media).

In embodiments, the (S) configured compound (or salt, e.g., apharmaceutically acceptable salt, thereof) is substantially free of(e.g., contains less than about 5% of, less than about 2% of, less thanabout 1%, less than about 0.5% of) a formula (I) compound (or saltthereof as described herein) that is (R) configured at the carbonattached to R^(A1) and R^(A2) (i.e., a formula (I) compound in which thecarbon attached to R^(A1) and R^(A2) has the (R) configuration). Forexample, the (S) configured compound can be an (S)-enantiomer that issubstantially free of its opposing (R) enantiomer. As another example,the (S) configured compound can be substantially free of a diastereomerin which the carbon attached to R^(A1) and R^(A2) has the (R)configuration. In certain embodiments, the (S) configured compound canbe additionally in substantially pure form (e.g., contains less thanabout 5% of, less than about 2% of, less than about 1%, less than about0.5% of other substances, including, for example, one or more of otherformula (I) compounds, non-formula (I) compounds, or biological media).

In certain embodiments, a formula (I) compound is (+) (dextrorotatory)when in the presence of plane polarized light.

In certain embodiments, a formula (I) compound is (−) (levororotatory)when in the presence of plane polarized light.

In embodiments, the (+) (dextrorotatory) compound is substantially freeof (e.g., contains less than about 5% of, less than about 2% of, lessthan about 1%, less than about 0.5%) a formula (I) compound (or saltthereof as described herein) that is (−) (levororotatory). In certainembodiments, the (+) (dextrorotatory) compound can be additionally insubstantially pure form (e.g., contains less than about 5% of, less thanabout 2% of, less than about 1%, less than about 0.5% of othersubstances, including, for example, one or more of other formula (I)compounds, non-formula (I) compounds, or biological media).

In embodiments, the (−) (levororotatory) compound is substantially freeof (e.g., contains less than about 5% of, less than about 2% of, lessthan about 1%, less than about 0.5%) a formula (I) compound (or saltthereof as described herein) that is (+) (dextrorotatory). In certainembodiments, the (−) (levororotatory) compound can be additionally insubstantially pure form (e.g., contains less than about 5% of, less thanabout 2% of, less than about 1%, less than about 0.5% of othersubstances, including, for example, one or more of other formula (I)compounds, non-formula (I) compounds, or biological media).

A is: (i) CR^(A1)R^(A2), wherein each of R^(A1) and R^(A2) isindependently selected from hydrogen, halo, C₁-C₃ alkyl, and OR⁹,wherein R⁹ is C₁-C₃ alkyl that is optionally substituted with hydroxylor C₁-C₃ alkoxy; or (ii) C═O.

A is CR^(A1)R^(A2), wherein each of R^(A1) and R^(A2) is, independently,hydrogen, halo, C₁-C₃ alkyl, or OR⁹.

In embodiments, one of R^(A1) and R^(A2) is independently selected fromhydrogen, halo, C₁-C₃ alkyl, and OR⁹; and the other of R^(A1) and R^(A2)is independently selected from halo, C₁-C₃ alkyl, and OR⁹.

In certain embodiments, one of R^(A1) and R^(A2) is halo, and the otherof R^(A1) and R^(A2) is hydrogen, halo, or C₁-C₃ alkyl. In embodiments,one of R^(A1) and R^(A2) is halo, and the other of R^(A1) and R^(A2) ishydrogen. For example, one of R^(A1) and R^(A2) is fluoro, and the otherof R^(A1) and R^(A2) is hydrogen.

In other embodiments, each of R^(A1) and R^(A2) is, independently, halo;e.g., each of R^(A1) and R^(A2) is fluoro.

In embodiments, one of R^(A1) and R^(A2) is —OH, and the other of R^(A1)and R^(A2) is hydrogen.

In embodiments, A is CR^(A1)R^(A2), wherein one of R^(A1) and R^(A2) isindependently selected from hydrogen, halo, C₁-C₃ alkyl, and OR⁹; andthe other of R^(A1) and R^(A2) is independently selected from halo,C₁-C₃ alkyl, and OR⁹; wherein R⁹ is hydrogen or C₁-C₃ alkyl that isoptionally substituted with hydroxyl or C₁-C₃ alkoxy.

In certain embodiments, one of R^(A1) and R^(A2) is OR⁹, and the otheris hydrogen, wherein R⁹ is hydrogen.

In embodiments, one of R^(A1) and R^(A2) is halo, and the other ofR^(A1) and R^(A2) is hydrogen or halo. For example, one of R^(A1) andR^(A2) is fluoro, and the other of R^(A1) and R^(A2) is hydrogen orfluoro.

In other embodiments, one of R^(A1) and R^(A2) is OR⁹; and the other ofR^(A1) and R^(A2) is C₁-C₃ alkyl. For example, one of R^(A1) and R^(A2)is OH; and the other of R^(A1) and R^(A2) is CH3.

Z is: (i) —NR¹⁰R¹¹; or (ii) —C(O)NR¹⁰R¹¹; or (iii) —OR¹²; or(iv)-S(O)_(n)R¹³, wherein n is 0, 1, or 2.

Z is —NR¹⁰R¹¹. In embodiments, one of R¹⁰ and R¹¹ is: (b) C₆-C₁₀ arylthat is optionally substituted with from 1-4R^(b); or (c) heteroarylcontaining from 5-14 ring atoms, wherein from 1-6 of the ring atoms isindependently selected from N, NH, N(C₁-C₃ alkyl), O, and S; and whereinsaid heteroaryl is optionally substituted with from 1-4R^(b); and theother of R¹⁰ and R¹¹ is hydrogen or C₁-C₆ alkyl.

Z is −OR¹² or —S(O)_(n)R¹³.

In embodiments, Z is —OR¹². In certain embodiments, R¹² is C₆-C₁₀ arylthat is optionally substituted with from 1-4R^(b).

In embodiments, R¹² is C₁-C₆ alkyl or C₁-C₆ haloalkyl (e.g., C₁-C₆alkyl), each of which is substituted with from 1-3R^(d). In otherembodiments, R¹² is other than C₁-C₆ alkyl or C₁-C₆ haloalkyl (e.g.,C₁-C₆ alkyl), each of which is unsubstituted or substituted with from1-3R^(d).

R³ can be selected from halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆haloalkyl, cyano, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆alkyl), and nitro. E.g., R³ can be halo (e.g., bromo). In embodiments,each of R¹, R², and R⁴ can be hydrogen.

L¹ can be C₁-C₃ straight chain alkylene, which is optionally substitutedwith from 1-2 independently selected R^(c). E.g., L¹ can be CH₂.

L² can be C₁-C₃ straight chain alkylene, which is optionally substitutedwith from 1-2 independently selected R^(c). E.g., L² can be CH₂.

Each of L¹ and L² can be, independently, C₁-C₃ straight chain alkylene,which is optionally substituted with from 1-2 independently selectedR^(c). E.g., each of L¹ and L² can be CH₂.

A can be CR^(A1)R^(A2), in which each of R^(A1) and R^(A2) is,independently, hydrogen, halo, C₁-C₃ alkyl, or OR⁹.

A can be CR^(A1)R^(A2), in which each of R^(A1) and R^(A2) is,independently, hydrogen, halo, or C₁-C₃ alkyl.

A can be CR^(A1)R^(A2), in which one of R^(A1) and R^(A2) is halo (e.g.,fluoro), and the other of R^(A1) and R^(A2) is, independently, hydrogen,halo, or C₁-C₃ alkyl (e.g., hydrogen).

A can be CR^(A1)R^(A2), in which one of R^(A1) and R^(A2) is halo (e.g.,fluoro), and the other of R^(A1) and R^(A2) is hydrogen.

One of R^(A1) and R^(A2) can be halo or OR⁹, and the other is hydrogen.

One of R^(A1) and R^(A2) can be OR⁹. In embodiments, the other of R^(A1)and R^(A2) can be as defined anywhere herein; e.g., the other of R^(A1)and R^(A2) can be hydrogen or C₁-C₃ alkyl. For example, one of R^(A1)and R^(A2) can be OR⁹, and the other of R^(A1) and R^(A2) is hydrogen.In embodiments, R⁹ can be hydrogen.

One of R^(A1) and R^(A2) can be halo. In embodiments, the other ofR^(A1) and R^(A2) can be as defined anywhere herein; e.g., the other ofR^(A1) and R^(A2) can be hydrogen, C₁-C₃ alkyl, or halo. For example,one of R^(A1) and R^(A2) can be halo (e.g., fluoro), and the other ofR^(A1) and R^(A2) is hydrogen.

The carbon attached to R^(A1) and R^(A2) can have the R configuration.

The carbon attached to R^(A1) and R^(A2) can have the S configuration.

Each of L¹ and L² is, independently, C₁-C₃ alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c). E.g., each of L¹and L² can be CH₂.

Z can be —NR¹⁰R¹¹.

One of R¹⁰ and R¹¹ can be C₆-C₁₀ aryl that is optionally substitutedwith from 1-4R^(b).

One of R¹⁰ and R¹¹ can be C₆-C₁₀ aryl that is optionally substitutedwith from 1-4R^(b), and the other is hydrogen or C₁-C₆ alkyl.

One of R¹⁰ and R¹¹ can be C₆-C₁₀ aryl that is optionally substitutedwith from 1-4R^(b), and the other is hydrogen. For example, one of R¹⁰and R¹¹ can be unsubstituted phenyl, and the other is hydrogen. Asanother example, one of R¹⁰ and R¹¹ can be phenyl that is substitutedwith 1R^(b), and the other is hydrogen. In embodiments, R^(b) can beC₁-C₆ alkoxy (e.g., OCH₃). For example, one of R¹⁰ and R¹¹ can be3-methoxyphenyl, and the other is hydrogen.

Z can be —OR¹². In embodiments, R¹² can be C₁-C₆ alkyl or C₁-C₆haloalkyl, each of which is optionally substituted with from 1-3R^(c).In other embodiments, R¹² can be C₆-C₁₀ aryl that is optionallysubstituted with from 1-4R^(b). For example, R¹² can be unsubstitutedphenyl.

Z can be —S(O)_(n)R¹³, in which n can be 0, 1, or 2. In otherembodiments, R¹³ can be C₆-C₁₀ aryl that is optionally substituted withfrom 1-4R^(b). For example, R¹³ can be unsubstituted phenyl.

Z can be heterocycloalkenyl containing from 5-6 ring atoms, wherein from1-3 of the ring atoms is independently selected from N, NH, N(C₁-C₆alkyl), NC(O)(C₁-C₆ alkyl), O, and S; and wherein saidheterocycloalkenyl is optionally substituted with from 1-4 independentlyselected R^(a).

R and R′ together with C₂ and C₃, respectively, form a fused phenyl ringhaving formula (II):

R⁶ can be selected from halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆haloalkyl, cyano, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆alkyl), and nitro. E.g., R⁶ can be halo (e.g., bromo). In embodiments,each of R⁵, R⁷, and R⁸ can be hydrogen. Any one or more of the R¹, R²,R³, R⁴, L¹, L², A, and Z embodiments described herein can be combinedwith any one or more of the R⁵, R⁶, R⁷, and R⁸ embodiments describedherein.

Each of L¹ and L² can be CH₂; A can be CR^(A1)R^(A2), wherein one ofR^(A1) and R^(A2) is OR⁹, and the other is hydrogen; Z is —NR¹⁰R¹¹; andeach of R¹⁰ and R¹¹ can be independently selected from: (a) hydrogen;(b) C₆-C₁₀ aryl that is optionally substituted with from 1-4R^(b); (d)C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is optionally substitutedwith from 1-3R^(d); and (f) C₂-C₆ alkenyl or C₂-C₆ alkynyl.

Each of R³ and R⁶ can be halo (e.g., bromo); and each of R¹, R², R⁴, R⁵,R⁷, and R⁸ can be hydrogen. R⁹ can be hydrogen. One of R¹⁰ and R¹¹ canbe C₆-C₁₀ aryl that is optionally substituted with from 1-4R^(b), andthe other is hydrogen. One of R¹⁰ and R¹¹ can be unsubstituted phenyl,and the other is hydrogen. One of R¹⁰ and R¹¹ can be phenyl that issubstituted with 1R^(b), and the other is hydrogen. R^(b) can be C₁-C₆alkoxy (e.g., OCH₃). One of R¹⁰ and R¹¹ can be 3-methoxyphenyl, and theother is hydrogen.

Each of L¹ and L² is CH₂; A is CR^(A1)R^(A2), wherein one of R^(A1) andR^(A2) is OR⁹, and the other is hydrogen; Z is —NR¹⁰R¹¹; and each of R¹⁰and R¹¹ is independently selected from: (a) hydrogen; (b) C₆-C₁₀ arylthat is optionally substituted with from 1-4R^(b); (d) C₁-C₆ alkyl orC₁-C₆ haloalkyl, each of which is optionally substituted with from1-3R^(d); and (f) C₂-C₆ alkenyl or C₂-C₆ alkynyl. Embodiment can includeone or more of the following features.

Each of R³ and R⁶ is halo (e.g., bromo); and each of R¹, R², R⁴, R⁵, R⁷,and R⁸ is hydrogen. R⁹ can be hydrogen. One of R¹⁰ and R¹¹ can be C₆-C₁₀aryl that is optionally substituted with from 1-4R^(b), and the other ishydrogen. One of R¹⁰ and R¹¹ can be unsubstituted phenyl, and the otheris hydrogen. One of R¹⁰ and R¹¹ can be phenyl that is substituted with1R^(b), and the other is hydrogen. R^(b) can be C₁-C₆ alkoxy (e.g.,OCH₃). One of R¹⁰ and R¹¹ can be 3-methoxyphenyl, and the other ishydrogen.

In embodiments, (A), (B), or (C) applies. In other embodiments, (A) and(B); or (A) and (C); or (B) and (C) applies. In still other embodiments,(A), (B), or (C) apply.

Each of R and R′ can be, independently, hydrogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl. Each of R and R′ can be, independently, C₁-C₆ alkyl (e.g.,each of R and R′ can be CH₃). Each of R and R′ can be hydrogen.

The compound having formula (I) can include any one or more of or beselected from:

-   R-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;-   S-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2-iminopyridin-1(2H)-yl)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylthio)propan-2-ol;-   N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)acetamide;-   5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(3-methoxyphenyl)-oxazolidin-2-one;-   N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-one;-   N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-methoxypropyl)-3-methoxyaniline;-   1-(3,6-Dimethyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;-   1-(3-Bromo-6-methyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;-   1-(3,6-Dichloro-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;-   1-(5-bromo-2,3-dimethyl-1H-indol-1-yl)-3-(phenylamino)propan-2-ol;-   1-(3,6-Dibromo-9H-pyrido[3,4-b]indol-9-yl)-3-(phenylamino)propan-2-ol;-   1-(3-Azidophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;-   1,3-Bis(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;-   1-(9H-Carbazol-9-yl)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;-   3-(3,6-Dibromo-9H-carbazol-9-yl)-2-hydroxy-N-(3-methoxyphenyl)-propanamide;-   Ethyl    5-(2-Hydroxy-3-(3-methoxyphenylamino)propyl)-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate;-   4-(3,6-dibromo-9H-carbazol-9-yl)-1-(phenylamino)butan-2-ol;-   N-(3-(3,6-dibromo-9H-carbazol-9-yl)propyl)aniline;-   1-(3,6-dibromo-9H-carbazol-9-yl)-4-(phenylamino)butan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-2-ylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-((3-methoxyphenyl)(methyl)-amino)propan-2-ol;-   3-(3,6-dibromo-9H-carbazol-9-yl)-1-(3-methoxyphenylamino)-1-(methylthio)propan-2-one;-   3-amino-1-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)pyridinium;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyrimidin-2-ylamino)propan-2-ol;-   N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxy-N-methylaniline;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-methoxypropan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-4-phenylbutan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(1H-indol-1-yl)propan-2-ol;-   3-(1-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)propan-1-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-ethoxyphenylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3,5-dimethyl-1H-pyrazol-1-yl)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfinyl)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;-   1-(3-bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;-   N-(5-(3-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropylamino)phenoxy)pentyl)-2-(7-(dimethylamino)-2-oxo-2H-chromen-4-yl)acetamide;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;-   N-(2-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropoxy)ethyl)-acetamide;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-3-ylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-4-ylamino)propan-2-ol;-   1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(phenylamino)propan-2-ol;-   N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2,2-difluoropropyl)-3-methoxyaniline;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(o-tolylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(m-tolylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2-methoxyphenylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(naphthalen-1-ylamino)propan-2-ol;-   1-(4-bromophenylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol;-   1-(4-bromophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(4-ethoxyphenylamino)propan-2-ol;-   1-(4-chlorophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenethylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2-hydroxyethylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2,4-dimethoxyphenylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2,3-dimethylphenylamino)propan-2-ol;-   1-(2-chlorophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;-   1-(tert-butylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(isopropylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(4-methoxyphenylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(m-tolylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3,5-dimethylphenylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3,4-dimethylphenylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3,4-dimethylphenylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2,5-dimethylphenylamino)propan-2-ol;-   1-(4-bromophenylamino)-3-(2,3-dimethyl-1H-indol-1-yl)propan-2-ol;-   1-(2,3-dimethyl-1H-indol-1-yl)-3-(4-methoxyphenylamino)propan-2-ol;-   1-(2,3-dimethyl-1H-indol-1-yl)-3-(4-ethoxyphenylamino)propan-2-ol;-   1-(2,3-dimethyl-1H-indol-1-yl)-3-(p-tolylamino)propan-2-ol;-   1-(2,3-dimethyl-1H-indol-1-yl)-3-(phenylamino)propan-2-ol oxalate;-   1-(1H-indol-1-yl)-3-(4-methoxyphenylamino)propan-2-ol hydrochloride;-   1-(1H-indol-1-yl)-3-(phenylamino)propan-2-ol oxalate;-   1-(3,4-dihydro-1H-carbazol-9(2H)-yl)-3-(m-tolylamino)propan-2-ol;-   1-(9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;-   1-(3,6-dichloro-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;-   1-(9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol;-   1-(3,6-dichloro-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol;-   N-(4-(3-(9H-carbazol-9-yl)-2-hydroxypropoxy)phenyl)acetamide;-   1-(9H-carbazol-9-yl)-3-phenoxypropan-2-ol;-   1-(9H-carbazol-9-yl)-3-(4-methoxyphenylamino)propan-2-ol;-   1-(benzylamino)-3-(9H-carbazol-9-yl)propan-2-ol;-   methyl 4-(3-(9H-carbazol-9-yl)-2-hydroxypropoxy)benzoate;-   1-(9H-carbazol-9-yl)-3-(4-methoxyphenoxy)propan-2-ol;-   1-amino-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;-   (S)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;-   (R)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;-   3,6-dibromo-9-(2-fluoro-3-phenoxypropyl)-9H-carbazole;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-2-methylpropan-2-ol;-   1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(3-methoxyphenylamino)propan-2-ol;-   1-(4-azidophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;-   1-(3-azido-6-bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;-   1-(3,6-dibromo-9H-carbazol-9-yl)-3-(4-methoxyphenoxy)propan-2-ol;-   1-(3,6-dichloro-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;-   3,6-dibromo-9-(2-fluoro-3-(phenylsulfonyl)propyl)-9H-carbazole;-   S)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl) propan-2-ol;-   (R)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;-   1-(3,6-dicyclopropyl-9H-carbazol-9-yl)-3-(phenylamino) propan-2-ol;-   1-(3,6-diiodo-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;-   1-(3,6-diethynyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)    propan-2-ol;-   9-(2-hydroxy-3-(3-methoxyphenylamino)propyl)-9H-carbazole-3,6-dicarbonitrile;-   N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)aniline;-   3,6-dibromo-9-(2,2-difluoro-3-phenoxypropyl)-9H-carbazole;-   N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-methoxyaniline;-   N-(2-bromo-3-(3,6-dibromo-9H-carbazol-9-yl)propyl)-N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide;-   Ethyl    2-(4-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropylamino)phenoxy)acetate;    and-   N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-(2-(2-methoxyethoxy)ethoxy)aniline;

or a salt (e.g., a pharmaceutically acceptable salt) thereof (or any oneor a subset thereof, e.g., as delineated in the claims).

In certain embodiments, the compound having formula (I) can be1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol; or a salt(e.g., a pharmaceutically acceptable salt) thereof.

In certain embodiments, the compound having formula (I)can beR-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;or a salt (e.g., a pharmaceutically acceptable salt) thereof. Inembodiments,R-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-olor a salt (e.g., a pharmaceutically acceptable salt) thereof can besubstantially free of (e.g., contains less than about 5% of, less thanabout 2% of, less than about 1%, less than about 0.5% of)S-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-olor a salt (e.g., a pharmaceutically acceptable salt) thereof.

In certain embodiments, the compound having formula (I) can beS-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;or a salt (e.g., a pharmaceutically acceptable salt) thereof. Inembodiments,S-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-olor a salt (e.g., a pharmaceutically acceptable salt) thereof can besubstantially free of (e.g., contains less than about 5% of, less thanabout 2% of, less than about 1%, less than about 0.5% of)R-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-olor a salt (e.g., a pharmaceutically acceptable salt) thereof.

In certain embodiments, the compound having formula (I) can be the (+)(dextrorotatory) enantiomer of1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol asdescribed herein or a salt (e.g., a pharmaceutically acceptable salt)thereof. See, e.g., Example 1a and 1b. In embodiments, the (+)(dextrorotatory) enantiomer of1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol asdescribed herein or a salt (e.g., a pharmaceutically acceptable salt)thereof can be substantially free of (e.g., contains less than about 5%of, less than about 2% of, less than about 1%, less than about 0.5% of)the (−) (levorotatory) enantiomer of1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol asdescribed herein or a salt (e.g., a pharmaceutically acceptable salt)thereof.

In certain embodiments, the compound having formula (I) can be the (−)(levorotatory) enantiomer of1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol asdescribed herein or a salt (e.g., a pharmaceutically acceptable salt)thereof. See, e.g., Example 1a and 1b. In embodiments, the (−)(levorotatory) enantiomer of1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol asdescribed herein or a salt (e.g., a pharmaceutically acceptable salt)thereof can be substantially free of (e.g., contains less than about 5%of, less than about 2% of, less than about 1%, less than about 0.5% of)the (+) (dextrorotatory) enantiomer of1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol asdescribed herein or a salt (e.g., a pharmaceutically acceptable salt)thereof.

The methods can further include detecting a resultant neurotrophism(e.g., neurogenesis; and/or determining that the patient has aberrantneurotrophism, particularly aberrant neurogenesis, particularly aberranthippocampal neurogenesis, or a disease or disorder associated therewith,particularly by detecting and/or diagnosing the same.

The methods can further include detecting a resultant neurotrophism.

The methods can further include detecting determining that the subjecthas aberrant neurogenesis or death of neurons or a disease or disorderassociated therewith, by detecting the same in said subject.

The methods can further include detecting a resultant hippocampalneurogenesis.

The disease, disorder, or condition can be a neuropsychiatric andneurodegenerative disease, including (but not limited to) schizophrenia,major depression, bipolar disorder, normal aging, epilepsy, traumaticbrain injury, post-traumatic stress disorder, Parkinson's disease,Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophiclateral sclerosis, Huntington's disease, stroke, radiation therapy,chronic stress, and abuse of neuro-active drugs, such as alcohol,opiates, methamphetamine, phencyclidine, and cocaine.

In some embodiments, the compounds having formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof provide at least about 27(×10⁻⁰⁶) BrdU+ cells/mm³ dentate gyms when evaluated in the assaydescribed in conjunction with Table 1 (i.e., evaluated forpro-neurogenic efficacy/neuroprotection in our standard in vivo assay at10 μM concentration in four 12 week old adult male C57/B16 mice.

In some embodiments, the compounds having formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof provide at least about 19(×10⁻⁰⁶) BrdU+ cells/mm³ dentate gyms when evaluated in the assaydescribed in conjunction with Table 1.

In some embodiments, the compounds having formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof provide from about 18 to about30 (e.g., 18-27, 19-26, 20-25, 27-30, 27-29) (×10⁻⁰⁶) BrdU+ cells/mm³dentate gyms when evaluated in the assay described in conjunction withTable 1.

In some embodiments, the compounds having formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof provide from about 18 to about26 (e.g., 19-26, 20-25) (×10⁰⁶) BrdU+ cells/mm³ dentate gyms whenevaluated in the assay described in conjunction with Table 1.

In some embodiments, the compounds having formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof provide from about 27 to about30 (e.g., 27-29) (×10⁰⁶) BrdU+ cells/mm³ dentate gyms when evaluated inthe assay described in conjunction with Table 1.

In embodiments, a composition (e.g., a pharmaceutical composition) caninclude an amount effective to achieve the levels described above.

In embodiments, any compound, composition, or method described hereincan also include any one or more of the other features delineated in thedetailed description and/or in the claims.

DEFINITIONS

The term “mammal” includes organisms, which include mice, rats, cows,sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans.

“An effective amount” refers to an amount of a compound that confers atherapeutic effect (e.g., treats, e.g., controls, relieves, ameliorates,alleviates, or slows the progression of; or prevents, e.g., delays theonset of or reduces the risk of developing, a disease, disorder, orcondition or symptoms thereof) on the treated subject. The therapeuticeffect may be objective (i.e., measurable by some test or marker) orsubjective (i.e., subject gives an indication of or feels an effect). Aneffective amount of the compound described above may range from about0.01 mg/kg to about 1000 mg/kg, (e.g., from about 0.1 mg/kg to about 100mg/kg, from about 1 mg/kg to about 100 mg/kg). Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents.

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

In general, and unless otherwise indicated, substituent (radical) prefixnames are derived from the parent hydride by either (i) replacing the“ane” in the parent hydride with the suffixes “yl,” “diyl,” “triyl,”“tetrayl,” etc.; or (ii) replacing the “e” in the parent hydride withthe suffixes “yl,” “diyl,” “triyl,” “tetrayl,” etc. (here the atom(s)with the free valence, when specified, is (are) given numbers as low asis consistent with any established numbering of the parent hydride).Accepted contracted names, e.g., adamantyl, naphthyl, anthryl,phenanthryl, furyl, pyridyl, isoquinolyl, quinolyl, and piperidyl, andtrivial names, e.g., vinyl, allyl, phenyl, and thienyl are also usedherein throughout. Conventional numbering/lettering systems are alsoadhered to for substituent numbering and the nomenclature of fused,bicyclic, tricyclic, polycyclic rings.

The following definitions are used, unless otherwise described. Specificand general values listed below for radicals, substituents, and ranges,are for illustration only; they do not exclude other defined values orother values within defined ranges for the radicals and substituents.Unless otherwise indicated, alkyl, alkoxy, alkenyl, and the like denoteboth straight and branched groups.

The term “alkyl” refers to a saturated hydrocarbon chain that may be astraight chain or branched chain, containing the indicated number ofcarbon atoms. For example, C₁-C₆ alkyl indicates that the group may havefrom 1 to 6 (inclusive) carbon atoms in it. Any atom can be optionallysubstituted, e.g., by one or more substitutents. Examples of alkylgroups include without limitation methyl, ethyl, n-propyl, isopropyl,and tert-butyl.

As used herein, the term “straight chain C_(n-m) alkylene,” employedalone or in combination with other terms, refers to a non-brancheddivalent alkyl linking group having n to m carbon atoms. Any atom can beoptionally substituted, e.g., by one or more substitutents. Examplesinclude methylene (i.e., —CH₂—).

The term “haloalkyl” refers to an alkyl group, in which at least onehydrogen atom is replaced by halo. In some embodiments, more than onehydrogen atom (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) arereplaced by halo. In these embodiments, the hydrogen atoms can each bereplaced by the same halogen (e.g., fluoro) or the hydrogen atoms can bereplaced by a combination of different halogens (e.g., fluoro andchloro). “Haloalkyl” also includes alkyl moieties in which all hydrogenshave been replaced by halo (sometimes referred to herein asperhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl). Any atomcan be optionally substituted, e.g., by one or more substituents.

As referred to herein, the term “alkoxy” refers to a group of formula—O(alkyl). Alkoxy can be, for example, methoxy (—OCH₃), ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 2-pentoxy,3-pentoxy, or hexyloxy. Likewise, the term “thioalkoxy” refers to agroup of formula —S(alkyl). Finally, the terms “haloalkoxy” and“thioalkoxy” refer to —O(haloalkyl) and —S(haloalkyl), respectively. Theterm “sulfhydryl” refers to —SH. As used herein, the term “hydroxyl,”employed alone or in combination with other terms, refers to a group offormula —OH.

The term “aralkyl” refers to an alkyl moiety in which an alkyl hydrogenatom is replaced by an aryl group. One of the carbons of the alkylmoiety serves as the point of attachment of the aralkyl group to anothermoiety. Any ring or chain atom can be optionally substituted e.g., byone or more substituents. Non-limiting examples of “aralkyl” includebenzyl, 2-phenylethyl, and 3-phenylpropyl groups.

The term “alkenyl” refers to a straight or branched hydrocarbon chaincontaining the indicated number of carbon atoms and having one or morecarbon-carbon double bonds. Any atom can be optionally substituted,e.g., by one or more substituents. Alkenyl groups can include, e.g.,vinyl, allyl, 1-butenyl, and 2-hexenyl. One of the double bond carbonscan optionally be the point of attachment of the alkenyl substituent.

The term “alkynyl” refers to a straight or branched hydrocarbon chaincontaining the indicated number of carbon atoms and having one or morecarbon-carbon triple bonds. Alkynyl groups can be optionallysubstituted, e.g., by one or more substituents. Alkynyl groups caninclude, e.g., ethynyl, propargyl, and 3-hexynyl. One of the triple bondcarbons can optionally be the point of attachment of the alkynylsubstituent.

The term “heterocyclyl” refers to a fully saturated monocyclic,bicyclic, tricyclic or other polycyclic ring system having one or moreconstituent heteroatom ring atoms independently selected from O, N (itis understood that one or two additional groups may be present tocomplete the nitrogen valence and/or form a salt), or S. The heteroatomor ring carbon can be the point of attachment of the heterocyclylsubstituent to another moiety. Any atom can be optionally substituted,e.g., by one or more substituents. Heterocyclyl groups can include,e.g., tetrahydrofuryl, tetrahydropyranyl, piperidyl(piperidino),piperazinyl, morpholinyl(morpholino), pyrrolinyl, and pyrrolidinyl. Byway of example, the phrase “heterocyclic ring containing from 5-6 ringatoms, wherein from 1-2 of the ring atoms is independently selected fromN, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S; and wherein saidheterocyclic ring is optionally substituted with from 1-3 independentlyselected R^(a)” would include (but not be limited to) tetrahydrofuryl,tetrahydropyranyl, piperidyl(piperidino), piperazinyl,morpholinyl(morpholino), pyrrolinyl, and pyrrolidinyl.

The term “heterocycloalkenyl” refers to partially unsaturatedmonocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groupshaving one or more (e.g., 1-4) heteroatom ring atoms independentlyselected from O, N (it is understood that one or two additional groupsmay be present to complete the nitrogen valence and/or form a salt), orS. A ring carbon (e.g., saturated or unsaturated) or heteroatom can bethe point of attachment of the heterocycloalkenyl substituent. Any atomcan be optionally substituted, e.g., by one or more substituents.Heterocycloalkenyl groups can include, e.g., dihydropyridyl,tetrahydropyridyl, dihydropyranyl, 4,5-dihydrooxazolyl,4,5-dihydro-1H-imidazolyl, 1,2,5,6-tetrahydro-pyrimidinyl, and5,6-dihydro-2H-[1,3]oxazinyl.

The term “cycloalkyl” refers to a fully saturated monocyclic, bicyclic,tricyclic, or other polycyclic hydrocarbon groups. Any atom can beoptionally substituted, e.g., by one or more substituents. A ring carbonserves as the point of attachment of a cycloalkyl group to anothermoiety. Cycloalkyl moieties can include, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, andnorbornyl(bicycle[2.2.1]heptyl).

The term “cycloalkenyl” refers to partially unsaturated monocyclic,bicyclic, tricyclic, or other polycyclic hydrocarbon groups. A ringcarbon (e.g., saturated or unsaturated) is the point of attachment ofthe cycloalkenyl substituent. Any atom can be optionally substitutede.g., by one or more substituents. Cycloalkenyl moieties can include,e.g., cyclohexenyl, cyclohexadienyl, or norbornenyl.

As used herein, the term “cycloalkylene” refers to a divalent monocycliccycloalkyl group having the indicated number of ring atoms.

As used herein, the term “heterocycloalkylene” refers to a divalentmonocyclic heterocyclyl group having the indicated number of ring atoms.

The term “aryl” refers to an aromatic monocyclic, bicyclic (2 fusedrings), or tricyclic (3 fused rings), or polycyclic (>3 fused rings)hydrocarbon ring system. One or more ring atoms can be optionallysubstituted, e.g., by one or more substituents. Aryl moieties include,e.g., phenyl and naphthyl.

The term “heteroaryl” refers to an aromatic monocyclic, bicyclic (2fused rings), tricyclic (3 fused rings), or polycyclic (>3 fused rings)hydrocarbon groups having one or more heteroatom ring atomsindependently selected from O, N (it is understood that one or twoadditional groups may be present to complete the nitrogen valence and/orform a salt), or S. One or more ring atoms can be optionallysubstituted, e.g., by one or more substituents.

Examples of heteroaryl groups include, but are not limited to,2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, acridinyl, benzo[b]thienyl,benzothiazolyl, β-carbolinyl, carbazolyl, coumarinyl, chromenyl,cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl,imidizolyl, indazolyl, indolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl,perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, andxanthenyl.

The terms “arylcycloalkyl” and “arylheterocyclyl” refer to bicyclic,tricyclic, or other polycyclic ring systems that include an aryl ringfused to a cycloalkyl and heterocyclyl, respectively. Similarly, theterms “heteroarylheterocyclyl,” and “heteroarylcycloalkyl” refer tobicyclic, tricyclic, or other polycyclic ring systems that include aheteroaryl ring fused to a heterocyclyl and cycloalkyl, respectively.Any atom can be substituted, e.g., by one or more substituents. Forexample, arylcycloalkyl can include indanyl; arylheterocyclyl caninclude 2,3-dihydrobenzofuryl, 1,2,3,4-tetrahydroisoquinolyl, and2,2-dimethylchromanyl.

The descriptors “C═O” or “C(O)” refers to a carbon atom that is doublybonded to an oxygen atom.

The term “oxo” refers to double bonded oxygen when a substituent oncarbon. When oxo is a substituent on nitrogen or sulfur, it isunderstood that the resultant groups has the structures N→O⁻ and S(O)and SO₂, respectively.

As used herein, the term “cyano,” employed alone or in combination withother terms, refers to a group of formula —CN, wherein the carbon andnitrogen atoms are bound together by a triple bond.

In general, when a definition for a particular variable includes bothhydrogen and non-hydrogen (halo, alkyl, aryl, etc.) possibilities, theterm “substituent(s) other than hydrogen” refers collectively to thenon-hydrogen possibilities for that particular variable.

The term “substituent” refers to a group “substituted” on, e.g., analkyl, haloalkyl, cycloalkyl, heterocyclyl, heterocycloalkenyl,cycloalkenyl, aryl, or heteroaryl group at any atom of that group. Inone aspect, the substituent(s) on a group are independently any onesingle, or any combination of two or more of the permissible atoms orgroups of atoms delineated for that substituent. In another aspect, asubstituent may itself be substituted with any one of the abovesubstituents.

Further, as used herein, the phrase “optionally substituted” meansunsubstituted (e.g., substituted with a H) or substituted. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substitutent. It is understood that substitution at agiven atom is limited by valency.

Descriptors such as “C₆-C₁₀ aryl that is optionally substituted withfrom 1-4 independently selected R^(b)” (and the like) is intended toinclude both an unsubstituted C₆-C₁₀ aryl group and a C₆-C₁₀ aryl groupthat is substituted with from 1-4 independently selected R^(b). The useof a substituent (radical) prefix names such as alkyl without themodifier “optionally substituted” or “substituted” is understood to meanthat the particular substituent is unsubstituted. However, the use of“haloalkyl” without the modifier “optionally substituted” or“substituted” is still understood to mean an alkyl group, in which atleast one hydrogen atom is replaced by halo.

In some embodiments, R^(b) can be as defined in any one, two, three, orall of (aa) through (dd). For example, R^(b) can be as defined in (aa)and (bb) or combinations thereof.

The phrase “Cy is a saturated, partially unsaturated or aromaticcarbocyclic or heterocyclic ring system” in the definition of R^(e) isunderstood to include each of the rings systems defined above (e.g., Cycan be coumarinyl or the ring component of biotin optionally substitutedas defined anywhere herein).

The details of one or more embodiments of the invention are set forth inthe description below. Other features and advantages of the inventionwill be apparent from the description and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Pulse-chase analysis of BrdU-labeling identified magnitude andtiming of cell death following birth of new neurons in the dentate gyms.12 week old wild type male C57/B6 mice were individually housed withoutaccess to running wheels and injected on day 0 with BrdU (50 mg/kg,i.p.). Neural precursor cell proliferation in the dentate gyms (DG)subgranular zone (SGZ) and granular layer (GL) was subsequentlymonitored through immunohistochemistry for BrdU on days 1, 5, 10, 15,20, and 25 days post-injection. Four mice were evaluated at each timepoint, and 25-30 adjacent coronal sections through the hippocampus(progressing posteriorly from the point where the suprapyramidal andinfrapyramidal blades are joined at the crest region and the dentategyms is oriented horizontally beneath the corpus callosum) from eachmouse were examined. On days 1 and 5, almost 100% of BrdU-positive cellswithin the DG were localized in the SGZ. The total number of cellsdecreased approximately 40% between days 1 and 5, in accordance with theappearance of apoptotic cell bodies in the SGZ. By day 10, some BrdUpositive cells had migrated into the GL, with no significant change intotal number of BrdU-positive cells in the DG. By day 15, BrdU-positivecells in the SGZ declined as the number of BrdU-positive cells in the GLstayed constant, suggesting that some of the cells migrating out of theSGZ and into the GL between days 10 and 15 underwent apoptosis. Thistrend continued through days 20-25. These results indicated that dailyinjection of BrdU over a one week period of continuous moleculeinfusion, a time period during which 40% of newborn cells in the SGZnormally die, would allow detection of compounds that enhance eitherproliferation or survival of newborn cells in the dentate gyms.

FIG. 2: Surgical placement of cannula and pumps did not affecthippocampal neurogenesis or survival of newborn neurons on thecontralateral side of the brain. Mice infused with vehicle (artificialcerebrospinal fluid) over seven days by means of surgically implantedAlzet osmotic minipumps (Vehicle Infusion, n=5) displayed no differencein hippocampal neural precursor cell proliferation, as assessed by BrdUincorporation normalized for dentate gyms volume, from mice treatedidentically except not having undergone surgery (No Surgery, n=4). WhenAlzet osmotic minipumps were loaded with fibroblast growth factor 2(FGF-2; 10 mg/mL) (n=5), however, hippocampal neural precursor cellproliferation roughly doubled with respect to both of the other twogroups (*, p<0.001, Student's t test).

FIG. 3: Ectopic incorporation of BrdU served to eliminate molecules fromfurther consideration. Immunohistochemical staining of BrdU in thehippocampal field should normally be restricted to the SGZ of thedentate gyms, as shown on the left. The in vivo neurogenic screenemployed was designed to detect small molecules that selectivelystimulated BrdU incorporation into replicating cells of the SGZ.Infrequently, some compounds exhibited non-specific BrdU incorporationin ectopic regions, such as CA3, CA1, cortex, and striatum, as shown onthe right. Any molecules that demonstrated ectopic incorporation of BrdUwere eliminated from the study.

FIG. 4: Screening of 100 pools of 10 compounds identified 10 pools withpro-neurogenic efficacy. The total number of BrdU-labeled cells in thedentate gyms subgranular zone (SGZ) approximately doubled followingseven day infusion with fibroblast growth factor 2 (FGF-2; 10 mg/mL)(n=5) relative to mice infused with vehicle (artificial cerebrospinalfluid (aCSF) (n=5). Each pool of ten compounds was tested forpro-neurogenic efficacy over a 7 day period in two independent mice at10 μM concentration for each individual compound. Pools 7, 14, 18, 19,41, 53, 54, 61, 69 and 70 displayed comparable stimulation of neuralprecursor cell proliferation as FGF-2 infusion. The majority of poolsdisplayed no effect on hippocampal neural precursor cell proliferation.

FIG. 5: Re-evaluation of positive pools verified statisticalsignificance of enhanced BrdU-incorporation. Subsequent to their initialidentification, pools 7, 14, 18, 19, 41, 53, 54, 61, 69, and 70 werere-evaluated in 2 additional mice each. Results shown are average withSEM of all 4 mice evaluated for each compound. All pools significantly(*, P<0.001, Student's t test) stimulated neural precursor cellproliferation in the hippocampal dentate gyms SGZ relative to vehiclecontrol.

FIG. 6A, FIG. 6B and FIG. 6C: Pro-neurogenic pools were broken down toidentify individual pro-neurogenic compounds. FIG. 6A: In vivoevaluation of the ten individual compounds that composed pool #7revealed that compound #3 stimulated either the proliferation orsurvival of neural precursor cells in the SGZ, whereas the remainingindividual components of pool #7 did not. In this document this moleculeis referred to as ‘Example 45 Compound.’ Each compound was infused attwo different concentrations (100 μM (A and B) and 10 μM (C and D)) intwo mice each. Example 45 Compound showed either pro-neurogenic orneuroprotective activity at both concentrations. Below the graphs aretypical results of BrdU incorporation in the SGZ, which is notablygreater in animals infused with either Pool #7 or Example 45 Compound.FIG. 6B: Molecular formulas and weights of individual pro-neurogeniccompounds identified through the in vivo screen. FIG. 6C: Re-suppliedcompounds were evaluated in three mice per compound at 10 μMconcentration to verify that the pro-neurogenic or neuroprotectiveeffect on neural stem cells was not an artifact of storage conditions inthe UTSWMC chemical compound library. Re-supplied compounds wereverified to be 99% pure by mass spectrometry and shown to retain eitherpro-proliferative or neuroprotective properties in vivo in neural stemcells. All compounds significantly (*, P<0.001, Student's t test)stimulated neural precursor cell proliferation in the hippocampaldentate gyms SGZ relative to vehicle control.

FIG. 7: Neurogenic efficacy of orally administered Example 45 Compoundwas dose-related. The graph on the left shows that the concentration ofExample 45 Compound in brain tissue of mice that were administeredcompound by daily oral gavage for 7 consecutive days correlated with thedose of Example 45 Compound administered. The graph on the right showsthat pro-neurogenic or neuroprotective efficacy of Example 45 Compoundwas roughly double that of vehicle control at doses ranging from 5 to 40mg/kg. At decreasing dosage of Example 45 Compound the amount ofneurogenesis decreased accordingly, until it reached levels no greaterthan vehicle control at compound doses below 1.0 mg/kg. Results shownare the average obtained from analysis of 5 adult wild type male mice ateach dose.

FIG. 8: Analysis of molecules related structurally to Example 45Compound revealed a region of the compound that could be chemicallymodified without loss of in vivo activity. An in vivo SAR study wasconducted using 37 chemical analogs of Example 45 Compound (labeled onthe graph as P7C3A1-41), each evaluated in 4 or 5 adult C57/B6 malemice. Some analogs revealed activity comparable to the parent compound,whereas others showed significantly diminished activity, or evidence ofpro-neurogenic effect intermediate between vehicle and FGF controls.This exercise enabled identification of regions of the parent compoundthat might be amenable to chemical modification without loss ofactivity. As an example, Example 62 Compound retained robust activitywith the aniline ring of Example 45 Compound substituted by ananisidine. This derivative compound was exploited to yield a fluorescentderivative by attaching a coumarin moiety to the N-phenyl ring.

FIG. 9A and FIG. 9B: Activity of Example 62 Compound isenantiomer-specific. FIG. 9A: (+) and (−) enantiomers of Example 62Compound were prepared. FIG. 9B: Evaluation of Example 62 Compoundenantiomers showed that in vivo pro-neurogenic or neuroprotectiveefficacy was fully retained by the (+) enantiomer in a dose-dependentmanner, while the (−) enantiomer showed diminished activity. Eachenantiomer was evaluated at each dose in between 3 and 5 three month oldadult wild type male C57/B6 mice.

FIG. 10A and FIG. 10B: Example 45 Compound enhances the survival ofnewborn neurons in the dentate gyms. FIG. 10A: Immunohistochemicalstaining for doublecortin (DCX), an antigen specifically and transientlyexpressed in proliferating hippocampal neural precursor cells when theybecome irreversibly committed to neuronal differentiation, wassubstantially increased in newborn neurons in mice that wereadministered Example 45 Compound (20 mg/kg) daily for 30 days by oralgavage, relative to that seen in mice that received vehicle only. Theseresults are representative of 10 sections each from 5 mice in eachgroup, and demonstrate that Example 45 Compound specifically promotedhippocampal neurogenesis. FIG. 10B: Example 45 Compound enhanceshippocampal neurogenesis by promoting survival of newborn neurons. Threemonth old wild type C57/B6 male mice were exposed to orally-deliveredExample 45 Compound or vehicle for 30 days (n=5 animals/group),administered a single pulse of BrdU via IP injection (150 mg/kg), andthen sacrificed 1 hour, 1 day, 5 days or 30 days later forimmunohistochemical detection of BrdU incorporation into cells localizedin the subgranular layer of the dentate gyms. No significant differenceswere observed between groups at the 1 hour or 1 day time points, thoughat one day there was a trend towards increased BrdU+ cells in theExample 45 Compound-treated group. At the 5 day time point, by whichtime 40% of newborn neurons normally die, animals that received Example45 Compound showed a statistically significant (*, P<0.001, Student's ttest) 25% increase in BrdU+ cells compared to the vehicle-only controlgroup. This difference between groups progressed with time such thatmice that received a daily oral dose of Example 45 Compound for 30 days,starting 24 hours after the pulse administration of BrdU, exhibited a5-fold increase in the abundance of BrdU+ cells in the dentate gymsrelative to vehicle-only controls. In this longer-term trial, BrdU+cells were observed both in the SGZ and the granular layer of thedentate gyms.

FIG. 11: Quantification of short term (1 hour pulse) BrdU incorporationand cleaved-caspase 3 (CCSP3) formation in the dentate gyms showed thatNPAS3-deficient mice have the same rate of proliferation of newborncells in the dentate as wild type littermates (BrdU), but roughly twicethe level of programmed cell death (CCSP3) (*, P<0.01, Student's ttest). Three 6 week old male mice (NPAS3-deficient or wild typelittermates) in each group were evaluated.

FIG. 12A and FIG. 12B: Granule cell neurons in the dentate gyms ofNPAS3-deficient mice displayed morphological deficits in dendriticbranching and spine density. FIG. 12A: Golgi-Cox staining of the dentategyms illustrates that dendritic arborization of dentate gyms granulecell neurons in npas3^(−/−) mice is substantially less developed than inwild type littermates. Results shown are representative of 15 sectionsfrom five 12-14 week old adult male mice of each genotype. FIG. 12B: Inaddition to obviously reduced dendritic length and branching, granularneurons in the dentate gyms of npas3^(−/−) mice also exhibitedsignificantly reduced spine density relative to wild type littermates(*, P<0.00001, Student's t test). These genotype-specific differenceswere not exhibited by neurons in the CA1 region of the hippocampus.

FIG. 13A and FIG. 13B: In hippocampal slice preparation from npas3 mice,synaptic transmission was increased both in the outer molecular layer ofthe dentate gyms (FIG. 13A) and the CA1 region of the hippocampus (FIG.13B) relative to hippocampal slices from wild type mice. Extendedtreatment with Example 45 Compound normalized synaptic responses in thedentate gyms but not the CA1 region of npas3^(−/−) mice. Extendedtreatment with Example 45 Compound did not affect wild-type responses.Data are presented as the mean±SEM. Each group consisted of 1 or 2 slicepreparation from each of 5 mice.

FIG. 14: Example 45 Compound has pro-neurogenic or neuroprotectiveefficacy in the dentate gyms of NPAS3-deficient animals. Six 12 week oldnpas3^(−/−) mice were orally administered vehicle or Example 45 Compound(20 mg/kg/d) for 12 days, and also injected daily with BrdU (50 mg/kg).At the end of day 12, mice were sacrificed and tissue was stained forBrdU and doublecortin (DCX). BrdU staining showed that Example 45Compound increased the magnitude of neurogenesis in npas3^(−/−) mice byroughly 4-fold, as graphically represented above (*, P<0.001, Student'st test). DCX staining shows that Example 45 Compound also promoted moreextensive process formation in differentiating neurons of the adultdentate gyms in npas3^(−/−) mice.

FIG. 15: Golgi-Cox staining of neurons in the dentate gyms shows thatextended daily treatment of npas3^(−/−) mice with Example 45 Compound(20 mg/kg/d) enhanced dendritic arborization. Hi-power micrographs areshown on top, and a lower power micrograph illustrating the entiredentate gyms is shown below.

FIG. 16: Measured thickness of hippocampal subfields in npas3 and wildtype littermate mice that were treated with Example 45 Compound (20mg/kg/d) or vehicle every day from embryonic day 14 until 3 months ofage demonstrated that Example 45 Compound selectively increased thethickness of the dentate gyms granular cell layer to a level approachingwild type thickness (*, P<0.01, Student's t test), without affectingthickness of the pyramidal cell layers of CA1 or CA3 regions.

FIG. 17: Immunohistochemical detection of cleaved caspase 3 (CCSP3), amarker of apoptosis, showed elevated levels of programmed cell death inthe dentate gyms of NPAS3-deficient animals. Apoptosis inNPAS3-deficient animals was inhibited by treatment with Example 45Compound (20 mg/kg/d, p.o., for 12 days), whereas analogous treatmentwith vehicle alone had no effect. Images shown are representative of10-12 sections evaluated per animal, with 3-5 eight-week-old maleNPAS3-deficient mice per group.

FIG. 18: Cell viability assay after exposure of cultured primarycortical neurons to Aβ₍₂₅₋₃₅₎ for 48 hours shows that Example 45Compound protected neurons from cell death compared to vehicle-treated(control) samples. Observed protection was afforded with the (+)enantiomer of Example 62 Compound, but less so with the (−) enantiomer.Data are presented as the mean±SEM.

FIG. 19: Chemical structure of FASDP.

FIG. 20: Fluorescently-labeled Example 62 Compound, termed FASDP, wasexposed to cultured U20S osteoblast cells and observed to localize witha distribution that overlapped with that of Mitotracker dye. Thisobservation indicated that the site of action of Example 45 Compound islocalized in mitochondria.

FIG. 21A and FIG. 21B: Example 45 Compound acts mechanistically in themitochondria.

FIG. 21A: Example 45 Compound preserved mitochondrial membrane potentialfollowing exposure to the calcium ionophore A23187 in a dose dependentmanner as judged by fluorescent imaging of TMRM dye, a cell-permeant,cationic red-orange fluorescent dye that is readily sequestered byintact mitochondria. FIG. 21B: The protective effect of Example 62Compound was enantiomeric specific, with the (+) enantiomer retainingactivity more so than the (−) enantiomer.

FIG. 22A, FIG. 22B, FIG. 22C and FIG. 22D: Example 45 Compound ascompared to a known drug. FIG. 22A: Both Example 45 Compound and theDimebon anti-histamine enhanced hippocampal neurogenesis (FIG. 22B),protected cultured cortical neurons from Aβ₍₂₅₋₃₅₎-mediated cell death(FIG. 22C), and protected mitochondria from dissolution following toxicexposure to the calcium ionophore A23187 (FIG. 22D). In the in vivoassay of neurogenesis the Example 45 Compound exhibited a higher ceilingof efficacy than the Dimebon anti-histamine. In all three assays, theExample 45 Compound performed with greater relative potency than theDimebon anti-histamine.

FIG. 23A, FIG. 23B, FIG. 23C, FIG. 23D and FIG. 23E: Effect of Example45 Compound in aged rats. FIG. 23A: Example 45 Compound (20 mg/kg/d,i.p.) and BrdU (50 mg/kg, i.p.) were administered daily for 7 days to12-18 month old Fisher 344 rats (n=4 in each group). P7C3 promotedneural precursor cell proliferation by roughly 5 fold compared tovehicle. (*p<0.001, Students t test). DCX staining demonstrates thatP7C3 specifically promoted neuronal differentiation and dendriticbranching. These micrographs were taken at the same magnification. Scalebar=50 mm. Data are expressed as mean+/−SEM. FIG. 23B: Latency to findthe hidden platform in the Morris water maze task, as well as swim spend(FIG. 23C) in aged rats treated with P7C3 or vehicle both before andafter 2 months of treatment did not differ between groups. Nor didlocomotor activity (FIG. 23D) vary with treatment paradigm. Example 45Compound-mediated effects on body weight were independent of food intake(FIG. 23E), and treatment of aged rats with Example 45 Compound had noeffect on postfasting blood glucose levels (FIG. 23E).

FIG. 24A, FIG. 24B, FIG. 24C and FIG. 24D: Example 45 Compound EnhancesHippocampal Neurogenesis, Ameliorates Cognitive Decline, and PreventsWeight Loss in Terminally Aged Rats. FIG. 24A: Prior to treatment, bothgroups (n—23 for each group) showed similar frequency of crossingsthrough the goal platform. After 2 months of treatment, however, Example45 Compound-treated rats displayed a statistically significant increaseof crossings through the goal platform area relative to vehicle treatedrats. FIG. 24B: Example 45 Compound-treated rats displayed significantlyenhanced hippocampal neurogenesis, as assessed by BrdU incorporation,relative to vehicle treated rats. Many more of the BrdU-labeled cellswere noted to have migrated into the granular layer in Example 45Compound-treated rats in comparison to vehicle treated animals,consistent with their functional incorporation into the dentate gyms asproperly wired neurons. The scale bar represents 50 mM. FIG. 24C:Relative to vehicle-treated animals, Example 45 Compound-treated ratsdisplayed significantly lower number of cleaved caspase 3-positive cellsin the dentate gyms, indicating that P7C3 was capable of inhibitingapoptosis in the aged rat brain. The scale bar represents 50 mM. FIG.24D: Relative to vehicle-treated animals, Example 45 Compound-treatedrats were observed to maintain stable body weight as a function ofterminal aging. In all graphs data are expressed as mean±SEM.

FIG. 25A, FIG. 25B, FIG. 25C, FIG. 25D, FIG. 25E and FIG. 25F: Example45 Compound Preserves Mitochondrial Membrane Potential in Parallel toProneurogenic Activity U20S cells were loaded with tetramethylrhodaminemethyl ester (TMRM) dye and then exposed to the calcium ionophore A23187either in the presence or absence of test compounds 1 Example 45Compound (FIG. 25A) preserved mitochondrial membrane potential followingexposure to the calcium ionophore A23187 in a dose-dependent manner. Theprotective effect of P7C3 was enantiomeric specific. The (R)-enantiomerof another compound (FIG. 25B) blocked dye release at levels as low as 1nM, whereas the (5)-enantiomer (FIG. 25C) failed to block dye releaseeven at the highest drug dose tested (100 nM). A proneurogenic (FIG.25D) exhibited dye release protection at all doses tested, yet compoundsdevoid of proneurogenic activity (FIG. 25E and FIG. 25F) failed topreserve mitochondrial membrane potential at any test dose. Eachcompound was evaluated in triplicate with similar results.

FIG. 26: Example 45 Compound Preserves Mitochondrial Membrane Potentialin Cultured Primary Cortical Neurorls. Cortical neurons cultures fromrats on embryonic day 14 were loaded with tetramethylrhodamine methylester (TMRM) dye after 6 days of maturation. The top panels (no calciumionophore) show that the dye alone did not affect the health of neurons.The remaining panels are from cells that were exposed to the calciumionophore A23187 at time zero. With vehicle-alone, cortical neuronmitochondrial membrane potential was rapidly lost after exposure to theionophore. Escalating doses of Example 45 Compound (A) preservedmitochondrial membrane potential following exposure to the calciumionophore A23187 in a dose dependent manner, with full protectionachieved at 1 mM. The inactive compound (B) failed to preservemitochondrial membrane potential at any dose. Results shown arerepresentative of 10 fields analyzed in each of 2 experimental runs forall conditions.

DETAILED DESCRIPTION

This invention relates generally to stimulating neurogenesis (e.g.,post-natal neurogenesis, e.g., post-natal hippocampal neurogenesis)and/or promoting the survival of existing neurons by reducing neuronalcell death.

Compounds

In one aspect, this invention features compounds having general formula(I):

Here and throughout this specification, R¹, R², R³, R⁴, R, R′, L¹, L²,A, and Z can be as defined anywhere herein.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable sub-combination.

Thus, for ease of exposition, it is also understood that where in thisspecification, a variable (e.g., R¹) is defined by “as defined anywhereherein” (or the like), the definitions for that particular variableinclude the first occurring and broadest generic definition as well asany sub-generic and specific definitions delineated anywhere in thisspecification.

Variables R¹, R², R³, R⁴

In some embodiments, one or two of R¹, R², R³, and R⁴ (e.g., one of,e.g., R³) is selected from halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy,C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl,C₁-C₆ haloalkyl, cyano, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and nitro; and the others are hydrogen.

In certain embodiments, one or two of R¹, R², R³, and R⁴ (e.g., one of,e.g., R³) is selected from halo, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, cyano, and nitro; and the others are hydrogen.

In certain embodiments, one or two of R¹, R², R³, and R⁴ (e.g., one of,e.g., R³) is selected from halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; andthe others are hydrogen.

In certain embodiments, one or two of R¹, R², R³, and R⁴ (e.g., one of,e.g., R³) is selected from halo and C₁-C₆ alkyl; and the others arehydrogen.

In certain embodiments, one or two of R¹, R², R³, and R⁴ (e.g., one of,e.g., R³) is halo (e.g., bromo or chloro) and C₁-C₆ alkyl; and theothers are hydrogen.

In certain embodiments, one or two of R¹, R², R³, and R⁴ (e.g., one of,e.g., R³) is bromo; and the others are hydrogen.

In some embodiments, R³ is selected from halo, hydroxyl, sulfhydryl,C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy,C₁-C₆ alkyl, C₁-C₆ haloalkyl, cyano, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and nitro; and each of R¹, R², and R⁴ canbe as defined anywhere herein.

In certain embodiments, R³ is selected from halo, hydroxyl, sulfhydryl,C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy,C₁-C₆ alkyl, C₁-C₆ haloalkyl, cyano, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and nitro; and each of R¹, R², and R⁴ ishydrogen.

In some embodiments, R³ is selected from halo, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, cyano, and nitro; and each ofR¹, R², and R⁴ can be as defined anywhere herein.

In certain embodiments, R³ is selected from halo, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, cyano, and nitro; and each ofR¹, R², and R⁴ is hydrogen.

In some embodiments, R³ is selected from halo, C₁-C₆ alkyl, and C₁-C₆haloalkyl; and each of R¹, R², and R⁴ can be as defined anywhere herein.

In certain embodiments, R³ is selected from halo, C₁-C₆ alkyl, and C₁-C₆haloalkyl; and each of R¹, R², and R⁴ is hydrogen.

In some embodiments, R³ is selected from halo and C₁-C₆ alkyl; and eachof R¹, R², and R⁴ can be as defined anywhere herein.

In certain embodiments, R³ is selected from halo and C₁-C₆ alkyl; andeach of R¹, R², and R⁴ is hydrogen.

In some embodiments, R³ is halo (e.g., bromo or chloro); and each of R¹,R², and R⁴ can be as defined anywhere herein.

In certain embodiments, R³ is halo (e.g., bromo or chloro); and each ofR¹, R², and R⁴ is hydrogen.

In some embodiments, R³ is bromo; and each of R¹, R², and R⁴ can be asdefined anywhere herein.

In certain embodiments, R³ is bromo; and each of R¹, R², and R⁴ ishydrogen.

In some embodiments, each of R¹, R², R³, and R⁴ is independentlyselected from hydrogen, halo, and C₁-C₆ alkyl.

In certain embodiments, each of R¹, R², R³, and R⁴ is independentlyselected from hydrogen and halo(e.g., bromo or chloro).

In some embodiments, each of R¹, R², R³, and R⁴ is hydrogen.

In some embodiments, when any one or more of R¹, R², R³, and R⁴ can be asubstituent other than hydrogen, said substituent, or each of saidsubstituents, is other than C₁-C₆ alkyl (e.g., other than C₁-C₃ alkyl,e.g., other than CH₃).

Variable L¹

In some embodiments, L¹ is C₁-C₃ (e.g., C₁-C₂) straight chain alkylene,which is optionally substituted with from 1-2 independently selectedR^(c).

In certain embodiments, L¹ is methylene (i.e., —CH₂—). In otherembodiments, L¹ is methylene that is substituted with 1 or 2 (e.g., 1)independently selected R^(c). In embodiments, R^(c) is C₁-C₆ alkyl(e.g., C₁-C₃ alkyl, e.g., CH₃).

In certain embodiments, L¹ is ethylene (i.e., —CH₂CH₂—). In otherembodiments, L¹ is ethylene that is substituted with 1 or 2 (e.g., 1)independently selected R^(c). In embodiments, R^(c) is C₁-C₆ alkyl(e.g., C₁-C₃ alkyl, e.g., CH₃).

Variable L²

In some embodiments, L² is C₁-C₃ (e.g., C₁-C₂) straight chain alkylene,which is optionally substituted with from 1-2 independently selectedR^(c).

In certain embodiments, L² is methylene (i.e., —CH₂—). In otherembodiments, L¹ is methylene that is substituted with 1 or 2 (e.g., 1)independently selected R^(c). In embodiments, R^(c) is C₁-C₆ alkyl(e.g., C₁-C₃ alkyl, e.g., CH₃). In embodiments, R^(c) is C₁-C₆ alkoxy,C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, or C₁-C₆ thiohaloalkoxy. Forexample, R^(c) can be C₁-C₆ (e.g., C₁-C₃)thioalkoxy, such as —SCH₃.

In certain embodiments, L² is ethylene (i.e., —CH₂CH₂—). In otherembodiments, L² is ethylene that is substituted with 1 or 2 (e.g., 1)independently selected R^(c). For example, the ethylene carbon moreproximal to Z in formula (I) can be substituted as described in thepreceding paragraph.

In certain embodiments, L² is a bond that directly connects A in formula(I) to Z in formula (I).

Non-Limiting Combinations of Variables L¹ and L²

In some embodiments, each of L¹ and L² is, independently, C₁-C₃alkylene, which is optionally substituted with from 1-2 independentlyselected R^(c).

In certain embodiments, each of L¹ and L² is CH₂.

In certain embodiments, one of L¹ and L² is CH₂ (e.g., L¹), and theother (e.g., L²) is methylene that is substituted with 1 or 2 (e.g., 1)independently selected R^(c), in which R^(c) can be as defined anywhereherein.

In certain embodiments, each of L¹ and L² is methylene that issubstituted with 1 or 2 (e.g., 1) independently selected R^(c), in whichR^(c) can be as defined anywhere herein.

In some embodiments, L¹ is C₁-C₃ (e.g., C₁-C₂) straight chain alkylene,which is optionally substituted with from 1-2 independently selectedR^(c), and L² is a bond that directly connects A in formula (I) to Z informula (I). In embodiments, L¹ can be, for example, methylene (i.e.,—CH₂—) or methylene that is substituted with 1 or 2 (e.g., 1)independently selected R^(c) (e.g., C₁-C₆ alkyl, e.g., C₁-C₃ alkyl,e.g., CH₃).

Variable A

[I] In some embodiments, A is:

-   -   (i) CR^(A1)R^(A2), wherein each of R^(A1) and R^(A2) is        independently selected from hydrogen, halo, C₁-C₃ alkyl, or OR⁹;        or    -   (ii) C═O; or    -   (iv) heterocycloalkylene containing from 3-5 ring atoms, wherein        from 1-2 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heterocycloalkylene        is (a) substituted with 1 oxo; and (b) is optionally further        substituted with from 1-4 independently selected R^(a).

In some embodiments, A is CR^(A1)R^(A2), in which each of R^(A1) andR^(A2) is, independently, hydrogen, halo, C₁-C₃ alkyl, or OR⁹ (e.g.,hydrogen, halo, or OR⁹).

In certain embodiments, A can be CR^(A1)R^(A2), in which each of R^(A1)and R^(A2) is, independently, hydrogen, halo, or C₁-C₃ alkyl.

In certain embodiments, A can be CR^(A1)R^(A2), in which one of R^(A1)and R^(A2) is halo (e.g., fluoro), and the other of R^(A1) and R^(A2)is, independently, hydrogen, halo, or C₁-C₃ alkyl (e.g., hydrogen).

In certain embodiments, one of R^(A1) and R^(A2) is hydrogen. Inembodiments, one of R^(A1) and R^(A2) is halo or OR⁹, and the other ishydrogen.

In certain embodiments, one of R^(A1) and R^(A2) can be OR⁹. Inembodiments, the other of R^(A1) and R^(A2) can be as defined anywhereherein; e.g., the other of R^(A1) and R^(A2) can be hydrogen or C₁-C₃alkyl. For example, one of R^(A1) and R^(A2) can be OR⁹, and the otherof R^(A1) and R^(A2) is hydrogen. In embodiments, R⁹ can be hydrogen orR⁹ can be C₁-C₃ alkyl (e.g., CH₃).

In certain embodiments, one of R^(A1) and R^(A2) can be halo. Inembodiments, the other of R^(A1) and R^(A2) can be as defined anywhereherein; e.g., the other of R^(A1) and R^(A2) can be hydrogen, C₁-C₃alkyl, or halo. For example, one of R^(A1) and R^(A2) can be halo (e.g.,fluoro), and the other of R^(A1) and R^(A2) is hydrogen.

In embodiments, one of R^(A1) and R^(A2) is halo or OR⁹, and the otheris hydrogen.

For example, one of R^(A1) and R^(A2) can be OR⁹, and the other ishydrogen. In embodiments, R⁹ can be hydrogen. R⁹ can be C₁-C₃ alkyl(e.g., CH₃).

As another example, one of R^(A1) and R^(A2) can be halo (e.g., fluoro),and the other is hydrogen.

In other embodiments, each of R^(A1) and R^(A2) is a substituent otherthan hydrogen.

For example, each of R^(A1) and R^(A2) can be halo (e.g., fluoro).

As another example, one of R^(A1) and R^(A2) can be OR⁹ (e.g., in whichR⁹ is hydrogen), and the other is C₁-C₃ alkyl (e.g., CH₃).

As a further example, each of R^(A1) and R^(A2) can be C₁-C₃ alkyl(e.g., CH₃).

In still other embodiments, each of R^(A1) and R^(A2) is hydrogen.

Embodiments can further include any one or more of the followingfeatures.

When the carbon attached to R^(A1) and R^(A2) is substituted with fourdifferent substituents, the carbon attached to R^(A1) and R^(A2) canhave the R configuration.

When the carbon attached to R^(A1) and R^(A2) is substituted with fourdifferent substituents, the carbon attached to R^(A1) and R^(A2) canhave the S configuration.

[II] In some embodiments, A is C═O.

[III] In some embodiments, A is heterocycloalkylene containing from 3-5ring atoms, in which from 1-2 of the ring atoms is independentlyselected from N, NH, N(C₁-C₃ alkyl), O, and S; and wherein saidheterocycloalkylene is (a) substituted with 1 oxo (e.g., 1 oxo on a ringcarbon); and (b) is optionally further substituted with from 1-4independently selected R^(a).

In certain embodiments, A is heterocycloalkylene containing 5 ringatoms, in which from 1-2 of the ring atoms is independently selectedfrom N, NH, N(C₁-C₃ alkyl), O, and S; and wherein saidheterocycloalkylene is (a) substituted with 1 oxo; and (b) is optionallyfurther substituted with from 1-4 independently selected R^(a). Forexample, A can be:

Non-Limiting Combinations of Variables L¹, L², and A

In some embodiments:

A is (i) CR^(A1)R^(A2), wherein each of R^(A1) and R^(A2) isindependently selected from hydrogen, halo, C₁-C₃ alkyl, or OR⁹; or (ii)C═O; and

each of L¹ and L² is, independently, C₁-C₃ alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c).

In some embodiments:

A is CR^(A1)R^(A2), wherein each of R^(A1) and R^(A2) is independentlyselected from hydrogen, halo, C₁-C₃ alkyl, or OR⁹; and

each of L¹ and L² is, independently, C₁-C₃ alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c).

Embodiments can include one or more of the following features

Each of R^(A1) and R^(A2) can be as defined anywhere herein.

Each of L¹ and L² is CH₂.

One of L¹ and L² is CH₂ (e.g., L¹), and the other (e.g., L²) ismethylene that is substituted with 1 or 2 (e.g., 1) independentlyselected R^(c), in which R^(c) can be as defined anywhere herein. Forexample:

-   -   L¹ can be CH₂; and    -   One of R^(A1) and R^(A2) is hydrogen; and    -   L² can be methylene that is substituted with 1 or 2 (e.g., 1)        independently selected R^(c) (e.g., C₁-C₆ (e.g., C₁-C₃)alkyl,        such as CH₃; or C₁-C₆ (e.g., C₁-C₃)thioalkoxy, such as —SCH₃);

Each of L¹ and L² is methylene that is substituted with 1 or 2 (e.g., 1)independently selected R^(c), in which R^(c) can be as defined anywhereherein. For example:

-   -   each of R^(A1) and R^(A2) can be a substituent other than        hydrogen (e.g., one of which is CH₃), and    -   each of L¹ and L² is methylene that is substituted with C₁-C₃        alkyl, such as CH₃).

In some embodiments:

A is heterocycloalkylene containing from 3-5 (e.g., 5) ring atoms, inwhich from 1-2 of the ring atoms is independently selected from N, NH,N(C₁-C₃ alkyl), O, and S; and wherein said heterocycloalkylene is (a)substituted with 1 oxo; and (b) is optionally further substituted withfrom 1-4 independently selected R^(a); and

L¹ is C₁-C₃ (e.g., C₁-C₂) straight chain alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c), and

L² is a bond that directly connects A in formula (I) to Z in formula(I).

Variable Z

[I] In some embodiments, Z is:

-   -   (i) —NR¹⁰R¹¹; or    -   (ii) —C(O)NR¹⁰R¹¹; or    -   (iii) —OR¹²; or    -   (iv) —S(O)_(n)R¹³, wherein n is 0, 1, or 2; or    -   (v) heterocycloalkenyl containing from 5-6 ring atoms, wherein        from 1-3 of the ring atoms is independently selected from N, NH,        N(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkyl), O, and S; and wherein said        heterocycloalkenyl is optionally substituted with from 1-4        independently selected R^(a);    -   (vi) C₆-C₁₀ aryl that is optionally substituted with from 1-4        independently selected R^(b); or    -   (vii) heteroaryl containing from 5-14 ring atoms, wherein from        1-6 of the ring atoms is independently selected from N, NH,        N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl is        optionally substituted with from 1-4 independently selected        R^(b).

In certain embodiments, Z is as defined in (i), (iii), (iv), (v), (vi),or (vii) in the preceding paragraph.

In certain embodiments, Z is as defined in (i), (iii), (iv), (v), or(vii) in the preceding paragraph.

In certain embodiments, Z is as defined in (i), (iii), (v), or (vii) inthe preceding paragraph.

In certain embodiments, Z is as defined in (i), (iii), or (iv) in thepreceding paragraph.

In certain embodiments, Z is:

-   -   (i) —NR    -   (iii) —OR¹²; or    -   (v) heterocycloalkenyl containing from 5-6 ring atoms, wherein        from 1-3 of the ring atoms is independently selected from N, NH,        N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S; and wherein said        heterocycloalkenyl is optionally substituted with from 1-4        independently selected R^(a).

In certain embodiments, Z is: (i) —NR¹⁰R¹¹; or (iii) —OR¹².

In certain embodiments, Z is: (i) —NR¹⁰R¹¹; or (iv) —S(O)_(n)R¹³,wherein n is 0, 1, or 2.

In certain embodiments, Z is: (iii) —OR¹²; or (iv) —S(O)_(n)R¹³, whereinn is 0, 1, or 2.

In certain embodiments, Z does not include heterocyclyl (e.g., anitrogenous heterocyclyl, e.g., piperazinyl or piperidinyl) as part ofits structure (e.g., as a fused ring or attached to another ring by abond).

In certain embodiments, Z is other than heterocycloalkenyl containingfrom 5-6 ring atoms, wherein from 1-3 of the ring atoms is independentlyselected from N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S; andwherein said heterocycloalkenyl is optionally substituted with from 1-4independently selected R^(a).

In certain embodiments, Z is other than heteroaryl containing from 5-14ring atoms, wherein from 1-6 of the ring atoms is independently selectedfrom N, NH, N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl isoptionally substituted with from 1-4 independently selected R^(b) (e.g.,other than pyridyl).

[II] In some embodiments, Z is —NR¹⁰R¹¹.

[A] In some embodiments, one of R¹⁰ and R¹¹ is hydrogen, and the otherof R¹⁰ and R¹¹ is a substituent other than hydrogen.

In some embodiments, one of R¹⁰ and R¹¹ is hydrogen or a substituentother than hydrogen, and the other of R¹⁰ and R¹¹ is a substituent otherthan hydrogen.

In some embodiments, each of R¹⁰ and R¹¹ is a substituent other thanhydrogen.

In some embodiments, each of R¹⁰ and R¹¹ is hydrogen.

[B] In some embodiments, one of R¹⁰ and R¹¹ is independently selectedfrom the substituents delineated collectively in (b), (c), (g) through(k), and (l) below:

-   -   (b) C₆-C₁₀ aryl that is optionally substituted with from        1-4R^(b);    -   (c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6        of the ring atoms is independently selected from N, NH, N(C₁-C₃        alkyl), O, and S; and wherein said heteroaryl is optionally        substituted with from 1-4R^(b);    -   (g) C₈-C₁₄ arylcycloalkyl, wherein:        -   (1) the aryl portion is optionally substituted with from 1-4            independently selected R^(b), and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   (h) arylheterocyclyl containing from 8-14 ring atoms, wherein:        -   (1) the aryl portion from is optionally substituted with            from 1-4 independently selected R^(b), and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   (i) heteroarylheterocyclyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) from 1-2 of the ring atoms of the heterocyclyl portion            is independently selected from N, NH, N(C₁-C₆ alkyl),            NC(O)(C₁-C₆ alkyl), O, and S; and wherein said heterocyclyl            portion is optionally substituted with from 1-3            independently selected R^(a);    -   (j) heteroarylcycloalkyl containing from 8-14 ring atoms,        wherein:        -   (1) from 1-2 of the ring atoms of the heteroaryl portion is            independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;            and wherein said heteroaryl portion is optionally            substituted with from 1-3 independently selected R^(b); and        -   (2) the cycloalkyl portion is optionally substituted with            from 1-4 independently selected R^(a);    -   (k) C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, each of which is        optionally substituted with from 1-4 independently selected        R^(a); and    -   (l) C₇-C₁₂ aralkyl, wherein the aryl portion is optionally the        aryl portion from is optionally substituted with from 1-4        independently selected R^(b),    -   and the other of R¹⁰ and R¹¹ can be as defined anywhere herein.

In some embodiments, R¹⁰ and R¹¹ cannot be C₃-C₈ cycloalkyl or C₃-C₈cycloalkenyl, each of which is optionally substituted with from 1-4independently selected R^(a).

In some embodiments, one of R¹⁰ and R¹¹ is independently selected fromthe substituents delineated collectively in (b), (c), (g) through (j),and (1) above; and the other of R¹⁰ and R¹¹ can be as defined anywhereherein.

In some embodiments, one of R¹⁰ and R¹¹ is independently selected fromthe substituents delineated collectively in (b), (c), and (g) through(j); and the other of R¹⁰ and R¹¹ can be as defined anywhere herein.

In some embodiments, one of R¹⁰ and R¹¹ is independently selected from:

(b) C₆-C₁₀ aryl that is optionally substituted with from 1-4R^(b);

(c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of thering atoms is independently selected from N, NH, N(C₁-C₃ alkyl), O, andS; and wherein said heteroaryl is optionally substituted with from1-4R^(b);

-   -   and the other of R¹⁰ and R¹¹ can be as defined anywhere herein.

In some embodiments, one of R¹⁰ and R¹¹ is C₆-C₁₀ aryl (e.g., C₆) thatis optionally substituted with from 1-4 (e.g., 1-3, 1-2, or 1) R^(b);and the other of R¹⁰ and R¹¹ can be as defined anywhere herein.

In certain embodiments, R^(b) at each occurrence is independentlyselected from halo; or C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy;C₁-C₆ thiohaloalkoxy; C₁-C₆ alkyl, C₁-C₆ haloalkyl, —NH(C₁-C₆ alkyl),N(C₁-C₆ alkyl)₂, and —NHC(O)(C₁-C₆ alkyl), each of which is optionallysubstituted with from 1-3 independently selected R^(e).

In certain embodiments, R^(b) at each occurrence is independentlyselected from C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; andC₁-C₆ thiohaloalkoxy, each of which is optionally substituted with from1-3 independently selected R^(e). In embodiments, R^(b) can furtherinclude halo.

In certain embodiments, R^(b) at each occurrence is independentlyselected from C₁-C₆ alkoxy and C₁-C₆ haloalkoxy, each of which isoptionally substituted with from 1-3 independently selected R^(e). Inembodiments, R^(b) can further include halo.

In certain embodiments, R^(b) at each occurrence is independentlyselected from C₁-C₆ alkoxy, each of which is optionally substituted withfrom 1-3 independently selected R^(e). In embodiments, R^(b) is C₁-C₆alkoxy (e.g., OCH₃). In embodiments, R^(b) can further include halo.

In certain embodiments, one of R¹⁰ and R¹¹ is unsubstituted phenyl, andthe other of R¹⁰ and R¹¹ can be as defined anywhere herein.

In certain embodiments, one of R¹⁰ and R¹¹ is phenyl that is substitutedwith 1R^(b), and the other of R¹⁰ and R¹¹ can be as defined anywhereherein. R^(b) can be as defined anywhere herein (e.g., R^(b) can beC₁-C₆ alkoxy, e.g., OCH₃). For example, one of R¹⁰ and R¹¹ can be3-methoxyphenyl. In embodiments, R^(b) can further include halo.

[C] In some embodiments, when one of R¹⁰ and R¹¹ is independentlyselected from the substituents delineated collectively in (b), (c), (g)through (k), and (1) above, the other of R¹⁰ and R¹¹ can be:

(a) hydrogen; or

(d) C₁-C₆ alkyl or C₁-C₆ haloalkyl (e.g., C₁-C₆ alkyl), each of which isoptionally substituted with from 1-3R^(d); or

(e) —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆ haloalkyl), or —C(O)O(C₁-C₆ alkyl);or

(f) C₂-C₆ alkenyl or C₂-C₆ alkynyl.

In certain embodiments, the other of R¹⁰ and R¹¹ is:

(a) hydrogen; or

(d) C₁-C₆ alkyl or C₁-C₆ haloalkyl (e.g., C₁-C₆ alkyl), each of which isoptionally substituted with from 1-3R^(d); or

(e) —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆ haloalkyl), or —C(O)O(C₁-C₆ alkyl).

In certain embodiments, the other of R¹⁰ and R¹¹ is:

(a) hydrogen; or

(d) C₁-C₆ alkyl or C₁-C₆ haloalkyl (e.g., C₁-C₆ alkyl), each of which isoptionally substituted with from 1-3R^(d); or

(e) —C(O)(C₁-C₆ alkyl), or —C(O)(C₁-C₆ haloalkyl).

In certain embodiments, the other of R¹⁰ and R¹¹ can be:

(a) hydrogen; or

(d) C₁-C₆ alkyl (e.g., C₁-C₃ alkyl, e.g., CH₃), which is optionallysubstituted with from 1-3R^(d); or

(e) —C(O)(C₁-C₆ alkyl), e.g., C₁-C₃ alkyl, e.g., CH₃.

In certain embodiments, the other of R¹⁰ and R¹¹ can be:

(a) hydrogen; or

(d) C₁-C₆ alkyl (e.g., C₁-C₃ alkyl, e.g., CH₃), which is optionallysubstituted with from 1-3R^(d).

In certain embodiments, the other of R¹⁰ and R¹¹ can be hydrogen.

In certain embodiments, the other of R¹⁰ and R¹¹ can be (d) or (e) orany subset thereof.

[E] In some embodiments, one of R¹⁰ and R¹¹ is C₆-C₁₀ (e.g., C₆) arylthat is optionally substituted with from 1-4R^(b), and the other ishydrogen or C₁-C₆ alkyl (e.g., C₁-C₃ alkyl, e.g., CH₃).

In some embodiments, one of R¹⁰ and R¹¹ is C₆-C₁₀ (e.g., C₆) aryl thatis optionally substituted with from 1-4R^(b), and the other is hydrogen.

In certain embodiments, one of R¹⁰ and R¹¹ is unsubstituted phenyl, andthe other is hydrogen.

In certain embodiments, one of R¹⁰ and R¹¹ is phenyl that is substitutedwith 1R^(b), and the other is hydrogen. In embodiments, R^(b) is C₁-C₆alkoxy (e.g., C₁-C₃ alkoxy, e.g., OCH₃). For example, one of R¹⁰ and R¹¹is 3-methoxyphenyl, and the other is hydrogen.

[F] In some embodiments, each of R¹⁰ and R¹¹ cannot be optionallysubstituted naphthyl (e.g., each of R¹⁰ and R¹¹ cannot be unsubstitutednaphthyl). In embodiments, each of R¹⁰ and R¹¹ is other than optionallysubstituted naphthyl (e.g., unsubstituted naphthyl) when R and R′ aredefined according to definitions (1), (2), and (4); and A isCR^(A1)R^(A2) (e.g., CHOR⁹, e.g., CHOH), and each of L¹ and L² is C₁-C₃alkylene (e.g., each of L¹ and L² is CH₂).

[G] In some embodiments, one of R¹⁰ and R¹¹ is hydrogen, and the otheris heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of thering atoms is independently selected from N, NH, N(C₁-C₃ alkyl), O, andS; and wherein said heteroaryl is optionally substituted with from1-4R^(b).

In certain embodiments, one of R¹⁰ and R¹¹ is hydrogen, and the other isheteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ringatoms is independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;and wherein said heteroaryl is optionally substituted with from1-2R^(b).

[III] In some embodiments, Z is —OR¹².

In some embodiments, R¹² is C₁-C₆ alkyl or C₁-C₆ haloalkyl, each ofwhich is optionally substituted with from 1-3R^(c).

In some embodiments, R¹² is C₁-C₆ alkyl, which is optionally substitutedwith from 1-3R^(c).

In certain embodiments, R¹² is C₁-C₆ alkyl (e.g., C₁-C₃ alkyl, e.g.,CH₃).

In certain embodiments, R¹² is C₁-C₆ alkyl (e.g., C₁-C₃ alkyl, e.g.,CH₃), which is optionally substituted with from 1-3 (e.g., 1 or 2,e.g., 1) R^(c). In embodiments, each occurrence of R^(c) can beindependently selected from —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, and—NHC(O)(C₁-C₆ alkyl).

In some embodiments, R¹² is C₆-C₁₀ aryl that is optionally substitutedwith from 1-4 (e.g., 1-3, 1-2, or 1) R^(b).

In certain embodiments, R^(b) at each occurrence is independentlyselected from halo; or C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy;C₁-C₆ thiohaloalkoxy; C₁-C₆ alkyl, C₁-C₆ haloalkyl, —NH(C₁-C₆ alkyl),N(C₁-C₆ alkyl)₂, and —NHC(O)(C₁-C₆ alkyl), each of which is optionallysubstituted with from 1-3 independently selected R^(e).

In certain embodiments, R^(b) at each occurrence is independentlyselected from C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; andC₁-C₆ thiohaloalkoxy, each of which is optionally substituted with from1-3 independently selected R^(e).

In certain embodiments, R^(b) at each occurrence is independentlyselected from C₁-C₆ alkoxy and C₁-C₆ haloalkoxy, each of which isoptionally substituted with from 1-3 independently selected R^(e).

In certain embodiments, R^(b) at each occurrence is independentlyselected from C₁-C₆ alkoxy, each of which is optionally substituted withfrom 1-3 independently selected R^(e). In embodiments, R^(b) is C₁-C₆alkoxy (e.g., OCH₃).

In embodiments, R^(b) can further include halo.

In certain embodiments, R¹² is unsubstituted phenyl.

In certain embodiments, R¹² is phenyl that is substituted with 1R^(b).R^(b) can be as defined anywhere herein (e.g., R^(b) can be C₁-C₆alkoxy, e.g., OCH₃). For example, R¹² can be 3-methoxyphenyl.

[IV] In some embodiments, Z is —S(O)_(n)R¹³, in which n can be 0, 1, or2.

In some embodiments, R¹³ is C₆-C₁₀ aryl that is optionally substitutedwith from 1-4 (e.g., 1-3, 1-2, or 1) R^(b).

In certain embodiments, R^(b) at each occurrence is independentlyselected from halo; or C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy;C₁-C₆ thiohaloalkoxy; C₁-C₆ alkyl, C₁-C₆ haloalkyl, —NH(C₁-C₆ alkyl),N(C₁-C₆ alkyl)₂, and —NHC(O)(C₁-C₆ alkyl), each of which is optionallysubstituted with from 1-3 independently selected R^(e).

In certain embodiments, R^(b) at each occurrence is independentlyselected from C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; andC₁-C₆ thiohaloalkoxy, each of which is optionally substituted with from1-3 independently selected R^(e).

In certain embodiments, R^(b) at each occurrence is independentlyselected from C₁-C₆ alkoxy and C₁-C₆ haloalkoxy, each of which isoptionally substituted with from 1-3 independently selected R^(e).

In certain embodiments, R^(b) at each occurrence is independentlyselected from C₁-C₆ alkoxy, each of which is optionally substituted withfrom 1-3 independently selected R^(e). In embodiments, R^(b) is C₁-C₆alkoxy (e.g., OCH₃).

In embodiments, R^(b) can further include halo.

In certain embodiments, R¹³ is unsubstituted phenyl.

In certain embodiments, R¹³ is phenyl that is substituted with 1R^(b).R^(b) can be as defined anywhere herein (e.g., R^(b) can be C₁-C₆alkoxy, e.g., OCH₃). For example, R¹³ can be 3-methoxyphenyl.

In embodiments, R¹² and/or R¹³ cannot be substituted phenyl. Inembodiments, R¹² and/or R¹³ cannot be substituted phenyl when R and R′are defined according to definition (1); and A is CR^(A1) (e.g., CHOR⁹,e.g., CHOH), and each of L¹ and L² is C₁-C₃ alkylene (e.g., each of L¹and L² is CH₂).

[V] In some embodiments, Z is heterocycloalkenyl containing from 5-6ring atoms, wherein from 1-3 of the ring atoms is independently selectedfrom N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S; and whereinsaid heterocycloalkenyl is optionally substituted with from 1-4independently selected R^(a).

In certain embodiments, Z is heterocycloalkenyl containing 6 ring atoms,wherein from 1-3 of the ring atoms is independently selected from N, NH,N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S; and wherein saidheterocycloalkenyl is optionally substituted with from 1-4 independentlyselected R^(a).

In certain embodiments, from 1-3 of the ring atoms is independentlyselected from N, NH, N(C₁-C₆ alkyl), and NC(O)(C₁-C₆ alkyl).

In certain embodiments, le at each occurrence is, independently selectedfrom oxo, thioxo, ═NH, and ═N(C₁-C₆ alkyl), e.g., ═NH.

For example, Z can be:

[V] In some embodiments, Z is heteroaryl containing from 5-14 ringatoms, wherein from 1-6 of the ring atoms is independently selected fromN, NH, N(C₁-C₃ alkyl), O, and S; and wherein said heteroaryl isoptionally substituted with from 1-4R^(b).

In certain embodiments, Z is heteroaryl containing from 5-10 ring atoms,wherein from 1-4 of the ring atoms is independently selected from N, NH,and N(C₁-C₃ alkyl); and wherein said heteroaryl is optionallysubstituted with from 1-2R^(b).

Variables R and R′

[I] In some embodiments, R and R′ together with C₂ and C₃, respectively,form a fused phenyl ring having formula (II):

in which each of R⁵, R⁶, R⁷, and R⁸ is independently selected fromhydrogen, halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy,C₁-C₆ haloalkoxy, C₁-C₆ halothioalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl,cyano, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl),and nitro.

For purposes of clarification, it is understood that compounds in whichR and R′ together with C₂ and C₃, respectively, form a fused phenyl ringhaving formula (II) correspond to compounds having the following generalformula:

in which R¹, R², R³, R⁴, L¹, L², A, and Z can be as defined anywhereherein.

In some embodiments, one or two of R⁵, R⁶, R⁷, and R⁸ (e.g., one of,e.g., R⁶) is selected from halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy,C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl,C₁-C₆ haloalkyl, cyano, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), and nitro; and the others are hydrogen.

In certain embodiments, one or two of R⁵, R⁶, R⁷, and R⁸ (e.g., one of,e.g., R⁶) is selected from halo, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, cyano, and nitro; and the others are hydrogen.

In certain embodiments, one or two of R⁵, R⁶, R⁷, and R⁸ (e.g., one of,e.g., R⁶) is selected from halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; andthe others are hydrogen.

In certain embodiments, one or two of R⁵, R⁶, R⁷, and R⁸ (e.g., one of,e.g., R⁶) is selected from halo and C₁-C₆ alkyl; and the others arehydrogen.

In certain embodiments, one or two of R⁵, R⁶, R⁷, and R⁸ (e.g., one of,e.g., R⁶) is halo (e.g., bromo or chloro) and C₁-C₆ alkyl; and theothers are hydrogen.

In certain embodiments, one or two of R⁵, R⁶, R⁷, and R⁸ (e.g., one of,e.g., R⁶) is bromo; and the others are hydrogen.

In some embodiments, R⁶ is selected from halo, hydroxyl, sulfhydryl,C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy,C₁-C₆ alkyl, C₁-C₆ haloalkyl, cyano, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and nitro; and each of R⁵, R⁷, and R⁸ canbe as defined anywhere herein.

In certain embodiments, R⁶ is selected from halo, hydroxyl, sulfhydryl,C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy,C₁-C₆ alkyl, C₁-C₆ haloalkyl, cyano, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and nitro; and each of R⁵, R⁷, and R⁸ ishydrogen.

In some embodiments, R⁶ is selected from halo, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, cyano, and nitro; and each ofR¹, R², and R⁴ can be as defined anywhere herein.

In certain embodiments, R⁶ is selected from halo, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, cyano, and nitro; and each ofR⁵, R⁷, and R⁸ is hydrogen.

In some embodiments, R⁶ is selected from halo, C₁-C₆ alkyl, and C₁-C₆haloalkyl; and each of R⁵, R⁷, and R⁸ can be as defined anywhere herein.

In certain embodiments, R⁶ is selected from halo, C₁-C₆ alkyl, and C₁-C₆haloalkyl; and each of R⁵, R⁷, and R⁸ is hydrogen.

In some embodiments, R⁶ is selected from halo and C₁-C₆ alkyl; and eachof R⁵, R⁷, and R⁸ can be as defined anywhere herein.

In certain embodiments, R⁶ is selected from halo and C₁-C₆ alkyl; andeach of R⁵, R⁷, and R⁸ is hydrogen.

In some embodiments, R⁶ is halo (e.g., bromo or chloro); and each of R⁵,R⁷, and R⁸ can be as defined anywhere herein.

In certain embodiments, R⁶ is halo (e.g., bromo or chloro); and each ofR⁵, R⁷, and R⁸ is hydrogen.

In some embodiments, R⁶ is bromo; and each of R⁵, R⁷, and R⁸ can be asdefined anywhere herein.

In certain embodiments, R⁶ is bromo; and each of R⁵, R⁷, and R⁸ ishydrogen.

In some embodiments, each of R⁵, R⁶, R⁷, and R⁸ is independentlyselected from hydrogen, halo, and C₁-C₆ alkyl.

In certain embodiments, each of R⁵, R⁶, R⁷, and R⁸ is independentlyselected from hydrogen and halo(e.g., bromo or chloro).

In some embodiments, each of R⁵, R⁶, R⁷, and R⁸ is hydrogen.

In some embodiments, when any one or more of R⁵, R⁶, R⁷, and R⁸ can be asubstituent other than hydrogen, said substituent, or each of saidsubstituents, is other than C₁-C₆ alkyl (e.g., C₁-C₃ alkyl, e.g., CH₃).

Embodiments can include any one or more of the features describedanywhere herein, including (but not limited to) those described below.

{A}

Each of R¹, R², R³, and R⁴ can be as defined anywhere herein.

R³ is selected from halo, hydroxyl, sulfhydryl, C₁-C₆ alkoxy, C₁-C₆thioalkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thiohaloalkoxy, C₁-C₆ alkyl, C₁-C₆haloalkyl, cyano, —NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆alkyl), and nitro; and each of R¹, R², and R⁴ can be as defined anywhereherein (e.g., each of R¹, R², and R⁴ is hydrogen).

R³ is selected from halo and C₁-C₆ alkyl; and each of R¹, R², and R⁴ canbe as defined anywhere herein (e.g., each of R¹, R², and R⁴ ishydrogen).

R³ is halo (e.g., bromo or chloro); and each of R¹, R², and R⁴ can be asdefined anywhere herein (e.g., each of R¹, R², and R⁴ is hydrogen).

R³ is bromo; and each of R¹, R², and R⁴ can be as defined anywhereherein (e.g., each of R¹, R², and R⁴ is hydrogen).

Each of R¹, R², R³, and R⁴ is independently selected from hydrogen andhalo(e.g., bromo or chloro).

Each of R¹, R², R³, and R⁴ is hydrogen.

Each of L¹ and L² is, independently, C₁-C₃ alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c).

Each of L¹ and L² is CH₂.

One of L¹ and L² is CH₂ (e.g., L¹), and the other (e.g., L²) ismethylene that is substituted with 1 or 2 (e.g., 1) independentlyselected R^(c), in which R^(c) can be as defined anywhere herein.

Each of L¹ and L² is methylene that is substituted with 1 or 2 (e.g., 1)independently selected R^(c), in which R^(c) can be as defined anywhereherein.

L¹ is C₁-C₃ (e.g., C₁-C₂) straight chain alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c), and L² is a bondthat directly connects A in formula (I) to Z in formula (I).

{C}

One of R^(A1) and R^(A2) is OR⁹, and the other is hydrogen. Inembodiments, R⁹ can be hydrogen. R⁹ can be C₁-C₃ alkyl (e.g., CH₃).

One of R^(A1) and R^(A2) can be halo (e.g., fluoro), and the other ishydrogen.

Each of R^(A1) and R^(A2) can be a substituent other than hydrogen. Forexample, each of R^(A1) and R^(A2) can be halo (e.g., fluoro). Asanother example, one of R^(A1) and R^(A2) can be OR⁹ (e.g., in which R⁹is hydrogen), and the other is C₁-C₃ alkyl (e.g., CH₃).

Each of R^(A1) and R^(A2) is hydrogen.

A is CR^(A1)R^(A2), wherein each of R^(A1) and R^(A2) is independentlyselected from hydrogen, halo, C₁-C₃ alkyl, or OR⁹; and each of L¹ and L²is, independently, C₁-C₃ alkylene, which is optionally substituted withfrom 1-2 independently selected R^(c).

{D}

Z is —NR¹⁰R¹¹, in which R¹⁰ and R¹¹ can be as defined anywhere herein.

One of R¹⁰ and R¹¹ is C₆-C₁₀ aryl that is optionally substituted withfrom 1-4R^(b). In embodiments, the other of R¹⁰ and R¹¹ is hydrogen orC₁-C₃ alkyl (e.g., CH₃). In embodiments, the other of R¹⁰ and R¹¹ ishydrogen.

In certain embodiments, one of R¹⁰ and R¹¹ is unsubstituted phenyl, andthe other is hydrogen.

In certain embodiments, one of R¹⁰ and R¹¹ is phenyl that is substitutedwith 1R^(b), and the other is hydrogen. In embodiments, R^(b) is C₁-C₆alkoxy (e.g., C₁-C₃ alkoxy, e.g., OCH₃). For example, one of R¹⁰ and R¹¹is 3-methoxyphenyl, and the other is hydrogen.

Z is −OR¹² or —S(O)_(n)R¹³, in which R¹² and R¹³ can be as definedanywhere herein.

Embodiments can include features from any one, two, three, or four of{A}, {B}, {C}, and {D}; or any combinations thereof.

In some embodiments:

R³ is a substituent other than hydrogen (e.g., halo and C₁-C₆ alkyl;e.g., halo, e.g., bromo); and and each of R¹, R², and R⁴ can be asdefined anywhere herein (e.g., each of R¹, R², and R⁴ is hydrogen); and

R⁶ is a substituent other than hydrogen (e.g., halo and C₁-C₆ alkyl;e.g., halo, e.g., bromo); and and each of R⁵, R⁷, and R⁸ can be asdefined anywhere herein (e.g., each of R⁵, R⁷, and R⁸ is hydrogen).

In some embodiments:

R³ is a substituent other than hydrogen (e.g., halo and C₁-C₆ alkyl;e.g., halo, e.g., bromo); and and each of R¹, R², and R⁴ can be asdefined anywhere herein (e.g., each of R¹, R², and R⁴ is hydrogen); and

R⁶ is a substituent other than hydrogen (e.g., halo and C₁-C₆ alkyl;e.g., halo, e.g., bromo); and and each of R⁵, R⁷, and R⁸ can be asdefined anywhere herein (e.g., each of R⁵, R⁷, and R⁸ is hydrogen); and

A is CR^(A1)R^(A2), wherein each of R^(A1) and R^(A2) is independentlyselected from hydrogen, halo, C₁-C₃ alkyl, or OR⁹; and each of L¹ and L²is, independently, C₁-C₃ alkylene, which is optionally substituted withfrom 1-2 independently selected R^(c).

Embodiments can include any one or more features described herein (e.g.,as described under {B} and {C} above).

In some embodiments:

R³ is a substituent other than hydrogen (e.g., halo and C₁-C₆ alkyl;e.g., halo, e.g., bromo); and and each of R¹, R², and R⁴ can be asdefined anywhere herein (e.g., each of R¹, R², and R⁴ is hydrogen); and

R⁶ is a substituent other than hydrogen (e.g., halo and C₁-C₆ alkyl;e.g., halo, e.g., bromo); and and each of R⁵, R⁷, and R⁸ can be asdefined anywhere herein (e.g., each of R⁵, R⁷, and R⁸ is hydrogen); and

A is CR^(A1)R^(A2), wherein each of R^(A1) and R^(A2) is independentlyselected from hydrogen, halo, C₁-C₃ alkyl, or OR⁹; and each of L¹ and L²is, independently, C₁-C₃ alkylene, which is optionally substituted withfrom 1-2 independently selected R^(c); and

Z is —NR¹⁰R¹¹, in which R¹⁰ and R¹¹ can be as defined anywhere herein.

Embodiments can include any one or more features described herein (e.g.,as described under {B}, {C}, and {D} above).

In some embodiments:

each of L¹ and L² is CH₂;

A is CR^(A1)R^(A2), wherein one of R^(A1) and R^(A2) is OR⁹, and theother is hydrogen;

Z is —NR¹⁰R¹¹; and

each of R¹⁰ and R¹¹ is independently selected from

(a) hydrogen;

(b) C₆-C₁₀ aryl that is optionally substituted with from 1-4R^(b);

(d) C₁-C₆ alkyl or C₁-C₆ haloalkyl, each of which is optionallysubstituted with from 1-3R^(d);

(f) C₂-C₆ alkenyl or C₂-C₆ alkynyl.

Embodiments can include any one or more features described herein (e.g.,as described under {A}, {C}, and {D} above).

In some embodiments:

A is CR^(A1)R^(A2), in which each of R^(A1) and R^(A2) is,independently, hydrogen, halo, or C₁-C₃ alkyl; or

A is CR^(A1)R^(A2), in which one of R^(A1) and R^(A2) is halo (e.g.,fluoro), and the other of R^(A1) and R^(A2) is, independently, hydrogen,halo, or C₁-C₃ alkyl (e.g., hydrogen); or

A is CR^(A1)R^(A2), in which one of R^(A1) and R^(A2) is halo (e.g.,fluoro), and the other of R^(A1) and R^(A2) is hydrogen; and

R¹, R², R³, R⁴, L¹, L², and Z can be as defined anywhere herein; or asalt (e.g., pharmaceutically acceptable salt) thereof.

Embodiments can include features from any one, two, three, or four of{A}, {B}, {C}, and {D}; or any combinations thereof.

In some embodiments:

one of R^(A1) and R^(A2) can be OR⁹. In embodiments, the other of R^(A1)and R^(A2) can be as defined anywhere herein; e.g., the other of R^(A1)and R^(A2) can be hydrogen or C₁-C₃ alkyl. For example, one of R^(A1)and R^(A2) can be OR⁹, and the other of R^(A1) and R^(A2) is hydrogen.In embodiments, R⁹ can be hydrogen; and

R¹, R², R³, R⁴, L¹, L², and Z can be as defined anywhere herein; or asalt (e.g., pharmaceutically acceptable salt) thereof.

In embodiments, one or more of the following apply, e.g., when A is CHOHand Z is NR¹⁰R¹¹:

-   -   each of R³ and R⁶ is CH₃; and/or each of R³ and R⁶ is bromo;        and/or each of R³ and R⁶ is chloro; and/or one of R³ and R⁶ is        CH₃ (e.g., R⁶), and the other is bromo (e.g., R³);    -   each of R¹⁰ and R¹¹ is other than hydrogen;    -   each of R¹⁰ and R¹¹ is hydrogen;    -   one of R¹⁰ and R¹¹ is heteroaryl as defined anywhere herein;    -   L¹ and/or L² is C₂-C₃ alkylene (optionally substituted);    -   (B) and/or (C) applies.

Embodiments can include features from any one, two, three, or four of{A}, {B}, {C}, and {D}; or any combinations thereof.

In some embodiments, Z is other than NR¹⁰R¹¹; and R¹, R², R³, R⁴, L¹,L², Z, can be as defined anywhere herein; or a salt (e.g.,pharmaceutically acceptable salt) thereof. In embodiments, (B) and/or(C) applies. Embodiments can include features from any one, two, three,or four of {A}, {B}, {C}, and {D}; or any combinations thereof.

In some embodiments, Z is −OR¹² and/or —S(O)_(n)R¹³; and R¹, R², R³, R⁴,L¹, L², and A can be as defined anywhere herein; or a salt (e.g.,pharmaceutically acceptable salt) thereof. In embodiments, (B) and/or(C) applies. Embodiments can include features from any one, two, three,or four of {A}, {B}, {C}, and {D}; or any combinations thereof.

In some embodiments, A is (ii) C═O; and/or (iv) heterocycloalkylenecontaining from 3-5 ring atoms, wherein from 1-2 of the ring atoms isindependently selected from N, NH, N(C₁-C₃ alkyl), O, and S; and whereinsaid heterocycloalkylene is (a) substituted with 1 oxo; and (b) isoptionally further substituted with from 1-4 independently selectedR^(a); and R¹, R², R³, R⁴, L¹, L², and Z can be as defined anywhereherein; or a salt (e.g., pharmaceutically acceptable salt) thereof.Embodiments can include features from any one, two, three, or four of{A}, {B}, {C}, and {D}; or any combinations thereof.

[II] In some embodiments, each of R and R′ is, independently, hydrogen,C₁-C₆ alkyl, or C₁-C₆ haloalkyl.

In embodiments, R and R′ can each be the same or different.

In certain embodiments, each of R and R′ is, independently, C₁-C₆ alkyl,e.g., each of R and R′ is CH₃.

In other embodiments, each of R and R′ is hydrogen.

Embodiments can include any one or more of the features describedanywhere herein, including (but not limited to) those described inconjunction with Formula (III).

[III] In some embodiments, R and R′ together with C₂ and C₃,respectively, form a fused heterocyclic ring containing from 5-6 ringatoms, wherein from 1-2 of the ring atoms is independently selected fromN, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S; and wherein saidheterocyclic ring is optionally substituted with from 1-3 independentlyselected R^(a). For purposes of clarification and illustration, anon-limiting example of these compounds is provided below (formula(IV)):

in which R¹, R², R³, R⁴, L¹, L², A, and Z can be as defined anywhereherein. Here, R and R′ together with C₂ and C₃, respectively, form afused heterocyclic ring containing 5-6 ring atoms.

Embodiments can include any one or more of the features describedanywhere herein, including (but not limited to) those described inconjunction with Formula (III). In certain embodiments, R⁶³ can behydrogen or C₁-C₃ alkyl (e.g., CH₃).

In some embodiments, it is provided:

(i) each of L¹ and L² must be C₁-C₃ alkylene, which is optionallysubstituted with from 1-2 independently selected R^(c) when A is CH₂; or

(ii) Z must be other than heteroaryl containing from 5-14 (e.g., 5-6 or6)ring atoms, wherein from 1-6 of the ring atoms is independentlyselected from N, NH, N(C₁-C₃ alkyl), O, and S; and wherein saidheteroaryl is optionally substituted with from 1-4 independentlyselected R^(b); e.g., other than substituted pyridyl, e.g., other thanpyridyl substituted with C₁-C₃ alkyl (e.g., CH₃), e.g., other than 2 or6-methylpyridyl.

[IV] In some embodiments, R and R′ together with C₂ and C₃,respectively, form a fused C₅-C₆ cycloalkyl ring that is optionallysubstituted with from 1-4 independently selected R^(a). For purposes ofclarification and illustration, a non-limiting example of such compoundsis provided below (formula (V)):

in which R¹, R², R³, R⁴, L¹, L², A, and Z can be as defined anywhereherein. Here, R and R′ together with C₂ and C₃, respectively, form afused C₆ cycloalkyl ring. Embodiments can include any one or more of thefeatures described anywhere herein, including (but not limited to) thosedescribed in conjunction with Formula (III).

[V] In some embodiments, R and R′ together with C₂ and C₃, respectively,form a fused heteroaryl ring containing from 5-6 ring atoms, whereinfrom 1-2 of the ring atoms is independently selected from N, NH, N(C₁-C₃alkyl), O, and S; and wherein said heteroaryl ring is optionallysubstituted with from 1-3 independently selected R^(b). See, e.g., thetitle compound of Example 13. Embodiments can include any one or more ofthe features described anywhere herein, including (but not limited to)those described in conjunction with Formula (III).

Any genus, subgenus, or specific compound described herein can includeone or more of the stereochemistry features described herein (e.g., asdelineated in the Summary).

Compound Forms and Salts

The compounds of this invention may contain one or more asymmetriccenters and thus occur as racemates and racemic mixtures,enantiomerically enriched mixtures, single enantiomers, individualdiastereomers and diastereomeric mixtures. All such isomeric forms ofthese compounds are expressly included in the present invention. Thecompounds of this invention may also contain linkages (e.g.,carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) whereinbond rotation is restricted about that particular linkage, e.g.restriction resulting from the presence of a ring or double bond.Accordingly, all cis/trans and E/Z isomers and rotational isomers areexpressly included in the present invention. The compounds of thisinvention may also be represented in multiple tautomeric forms, in suchinstances, the invention expressly includes all tautomeric forms of thecompounds described herein, even though only a single tautomeric formmay be represented. All such isomeric forms of such compounds areexpressly included in the present invention.

Optical isomers can be obtained in pure form by standard proceduresknown to those skilled in the art, and include, but are not limited to,diastereomeric salt formation, kinetic resolution, and asymmetricsynthesis. See, for example, Jacques, et al., Enantiomers, Racemates andResolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of NotreDame Press, Notre Dame, Ind. 1972), each of which is incorporated hereinby reference in their entireties. It is also understood that thisinvention encompasses all possible regioisomers, and mixtures thereof,which can be obtained in pure form by standard separation proceduresknown to those skilled in the art, and include, but are not limited to,column chromatography, thin-layer chromatography, and high-performanceliquid chromatography.

The compounds of this invention include the compounds themselves, aswell as their salts and their prodrugs, if applicable. A salt, forexample, can be formed between an anion and a positively chargedsubstituent (e.g., amino) on a compound described herein. Suitableanions include chloride, bromide, iodide, sulfate, nitrate, phosphate,citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, asalt can also be formed between a cation and a negatively chargedsubstituent (e.g., carboxylate) on a compound described herein. Suitablecations include sodium ion, potassium ion, magnesium ion, calcium ion,and an ammonium cation such as tetramethylammonium ion. Examples ofprodrugs include C₆ alkyl esters of carboxylic acid groups, which, uponadministration to a subject, are capable of providing active compounds.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. As used herein, the term “pharmaceuticallyacceptable salt” refers to a salt formed by the addition of apharmaceutically acceptable acid or base to a compound disclosed herein.As used herein, the phrase “pharmaceutically acceptable” refers to asubstance that is acceptable for use in pharmaceutical applications froma toxicological perspective and does not adversely interact with theactive ingredient.

Examples of suitable acid salts include acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate,pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,propionate, salicylate, succinate, sulfate, tartrate, thiocyanate,tosylate and undecanoate. Other acids, such as oxalic, while not inthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts. Salts derived from appropriate bases include alkali metal (e.g.,sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl)₄⁺ salts. This invention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Water oroil-soluble or dispersible products may be obtained by suchquaternization. Salt forms of the compounds of any of the formulaeherein can be amino acid salts of carboxy groups (e.g. L-arginine,-lysine, -histidine salts).

Lists of suitable salts are found in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418;Journal of Pharmaceutical Science, 66, 2 (1977); and “PharmaceuticalSalts: Properties, Selection, and Use A Handbook; Wermuth, C. G. andStahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN3-906390-26-8] each of which is incorporated herein by reference intheir entireties.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the invention.

In addition to salt forms, the invention provides compounds which are ina prodrug form. Prodrugs of the compounds described herein are thosecompounds that undergo chemical changes under physiological conditionsto provide the compounds of the invention. Additionally, prodrugs can beconverted to the compounds of the invention by chemical or biochemicalmethods in an ex vivo environment. For example, prodrugs can be slowlyconverted to the compounds of the invention when placed in a transdermalpatch reservoir with a suitable enzyme or chemical reagent. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent drug. They may, for instance, be morebioavailable by oral administration than the parent drug. The prodrugmay also have improved solubility in pharmacological compositions overthe parent drug. A wide variety of prodrug derivatives are known in theart, such as those that rely on hydrolytic cleavage or oxidativeactivation of the prodrug. An example, without limitation, of a prodrugwould be a compound of the invention which is administered as an ester(the “prodrug”), but then is metabolically hydrolyzed to the carboxylicacid, the active entity. Additional examples include peptidylderivatives of a compound of the invention.

The invention also includes various hydrate and solvate forms of thecompounds.

The compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe invention, whether radioactive or not, are intended to beencompassed within the scope of the invention.

Synthesis

The compounds of present invention can be conveniently prepared inaccordance with the procedures outlined in the Examples section, fromcommercially available starting materials, compounds known in theliterature, or readily prepared intermediates, by employing standardsynthetic methods and procedures known to those skilled in the art.Standard synthetic methods and procedures for the preparation of organicmolecules and functional group transformations and manipulations can bereadily obtained from the relevant scientific literature or fromstandard textbooks in the field. It will be appreciated that wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures, etc.) are given,other process conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvent used, but such conditions can be determined by one skilled inthe art by routine optimization procedures. Those skilled in the art oforganic synthesis will recognize that the nature and order of thesynthetic steps presented may be varied for the purpose of optimizingthe formation of the compounds described herein.

Synthetic chemistry transformations (including protecting groupmethodologies) useful in synthesizing the compounds described herein areknown in the art and include, for example, those such as described in R.C. Larock, Comprehensive Organic Transformations, 2d. ed., Wiley-VCHPublishers (1999); P. G. M. Wuts and T. W. Greene, Protective Groups inOrganic Synthesis, 4th Ed., John Wiley and Sons (2007); L. Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wileyand Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995), and subsequent editionsthereof.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy (FT-IR),spectrophotometry (e.g., UV-visible), or mass spectrometry (MS), or bychromatography such as high performance liquid chromatography (HPLC) orthin layer chromatography (TLC).

Preparation of compounds can involve the protection and deprotection ofvarious chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene, et al., Protective Groups in OrganicSynthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein byreference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvents.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includespreparation of the Mosher's ester or amide derivative of thecorresponding alcohol or amine, respectively. The absolute configurationof the ester or amide is then determined by proton and/or ¹⁹F NMRspectroscopy. An example method includes fractional recrystallizationusing a “chiral resolving acid” which is an optically active,salt-forming organic acid. Suitable resolving agents for fractionalrecrystallization methods are, for example, optically active acids, suchas the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids. Resolution of racemicmixtures can also be carried out by elution on a column packed with anoptically active resolving agent (e.g., dinitrobenzoylphenylglycine).Suitable elution solvent compositions can be determined by one skilledin the art.

The compounds of the invention can be prepared, for example, using thereaction pathways and techniques as described below.

A series of carbazole 1,2-aminoalcohol compounds of formula 3 may beprepared by the method outlined in Scheme 1. The9-oxiranylmethyl-9H-carbazole of formula 2 may be prepared from anappropriately substituted carbazole of formula 1 and epichlorohydrin inthe presence of a strong base such as sodium hydride.

The oxiranyl ring of formula 2 may be opened in the presence of aprimary or secondary amine to produce the 1,2-amino alcohol of formula3. Such reactive primary or secondary amines can be, but are not limitedto, phenethylamine, 3-phenylallyl amine, and N-substituted piperazinesand the like.

Alternatively, a variety of carbazole 1,2-aminoalcohol compounds offormula 8 may be prepared by the method outlined in Scheme 2. Theepoxide of 9-oxiranylmethyl-9H-carbazole of formula 2 may be opened witha primary amine, H₂NR¹⁰, to produce the secondary aminoalcohol offormula 4 and then protected with an amine protecting group (P) such astert-butoxycarbonyl (Boc) to afford the protected aminoalcohol offormula 5. Next, the hydroxyl group of formula 5 may be alkylated with astrong base such as sodium hydride and an alkylating agent (RX) such asan alkyl halide, tosylate, triflate or mesylate to produce the ether offormula 6. Removal of the amine protecting group in the presence of asuitable acid can provide the desired OR ether compounds of formula 7.Finally, reductive alkylation of the secondary amine of formula 7 may beachieved in the presence of an aldehyde and a reducing agent such assodium cyano borohydride (NaCNBH₃) to provide the tertiary1,2-aminoalcohol of formula 8.

A series of substituted indole compounds of formula 11 and 12 may beprepared by the method outlined below in Scheme 3. Compounds of formula11 may be prepared by the alkylation of an indole of formula 9 with anepoxide A, for example with epichlorohydrin or epibromohydrin, in thepresence of a strong base such as potassium hydroxide (KOH) orn-butyllithium (n-BuLi) to produce the oxiranyl indole of formula 10.Next, opening of the epoxide of compounds of formula 10 with a primaryamine, substituted alcohol or thiol in the presence of a strong base ora mild Lewis acid such as lithium bromide (LiBr) or bismuth chloride(BiCl₃) can provide the alcohol of formula 11. Additionally, compoundsof formula 12 may be prepared by opening an epoxide B at the lesshindered position with the indole nitrogen of formula 9.

In addition, a variety of epoxide derivatives may be prepared byfollowing the methods outlined in Scheme 4. The secondary alcohol ofcompounds of formula 11 may be oxidized using an oxidizing agent orunder Swern-like oxidation conditions to provide the ketone of formula13 which can further undergo reductive amination to provide the amine ofcompound 14. Alternatively, the secondary alcohol may be converted intoan ester using a carboxylic acid anhydride (where Z═R″C(O)) or an ether(where Z=alklyl) using standard alkylation conditions to producecompounds of formula 15. Fluorine compounds of formula 16 may beprepared by reaction of the alcohol of formula 11 with a fluorinatingagent such as diethylaminosulfur trifluoride (DAST).Nitrogen-heteroarylated compounds of formula 17 may be prepared in thepresence of a catalytic amount of copper iodide and a heteroaryl iodidestarting from compounds of formula 11 (where Y═N). Finally, sulfoxidesand sulfones of formula 18 may be prepared under oxidative conditions,for example in the presence of m-chloroperoxybenzoic acid (m-CPBA),starting from sulfides of formula 11 (where Y═S).

Pharmaceutical Compositions

The term “pharmaceutically acceptable carrier” refers to a carrier oradjuvant that may be administered to a subject (e.g., a patient),together with a compound of this invention, and which does not destroythe pharmacological activity thereof and is nontoxic when administeredin doses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the compositions of this invention include, but are not limitedto, ion exchangers, alumina, aluminum stearate, lecithin,self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherolpolyethyleneglycol 1000 succinate, surfactants used in pharmaceuticaldosage forms such as Tweens or other similar polymeric deliverymatrices, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts, orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, andγ-cyclodextrin, or chemically modified derivatives such ashydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives mayalso be advantageously used to enhance delivery of compounds of theformulae described herein.

The compositions for administration can take the form of bulk liquidsolutions or suspensions, or bulk powders. More commonly, however, thecompositions are presented in unit dosage forms to facilitate accuratedosing. The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient. Typical unit dosage forms includeprefilled, premeasured ampules or syringes of the liquid compositions orpills, tablets, capsules, losenges or the like in the case of solidcompositions. In such compositions, the compound is usually a minorcomponent (from about 0.1 to about 50% by weight or preferably fromabout 1 to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

The amount administered depends on the compound formulation, route ofadministration, etc. and is generally empirically determined in routinetrials, and variations will necessarily occur depending on the target,the host, and the route of administration, etc. Generally, the quantityof active compound in a unit dose of preparation may be varied oradjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg,according to the particular application. In a particular embodiment,unit dosage forms are packaged in a multipack adapted for sequentialuse, such as blisterpack, comprising sheets of at least 6, 9 or 12 unitdosage forms. The actual dosage employed may be varied depending uponthe requirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small amounts until the optimumeffect under the circumstances is reached. For convenience, the totaldaily dosage may be divided and administered in portions during the dayif desired.

The following are examples (Formulations 1-4) of capsule formulations.

Capsule Formulations Capsule Formulation 1; Formulation 2; Formulation3; Formulation 4; Formulation mg/capsule mg/capsule mg/capsulemg/capsule Carbazole (solid 100 400 400 200 solution) Silicon Dioxide0.625 2.5 3.75 1.875 Magnesium 0.125 0.5 0.125 0.625 Stearate NF2Croscarmellose 11.000 44.0 40.0 20.0 Sodium NF Pluronic F68 NF 6.25025.0 50.0 25.0 Silicon Dioxide NF 0.625 2.5 3.75 1.875 Magnesium 0.1250.5 1.25 0.625 Stearate NF Total 118.750 475.00 475.00 475.00 CapsuleSize No. 4 No. 0 No. 0 No. 2

Preparation of Solid Solution

Crystalline carbazole (80 g/batch) and the povidone (NF K29/32 at 160g/batch) are dissolved in methylene chloride (5000 mL). The solution isdried using a suitable solvent spray dryer and the residue reduced tofine particles by grinding. The powder is then passed through a 30 meshscreen and confirmed to be amorphous by x-ray analysis.

The solid solution, silicon dioxide and magnesium stearate are mixed ina suitable mixer for 10 minutes. The mixture is compacted using asuitable roller compactor and milled using a suitable mill fitted with30 mesh screen. Croscarmellose sodium, Pluronic F68 and silicon dioxideare added to the milled mixture and mixed further for 10 minutes. Apremix is made with magnesium stearate and equal portions of themixture. The premix is added to the remainder of the mixture, mixed for5 minutes and the mixture encapsulated in hard shell gelatin capsuleshells.

Use

In one aspect, methods for treating (e.g., controlling, relieving,ameliorating, alleviating, or slowing the progression of) or methods forpreventing (e.g., delaying the onset of or reducing the risk ofdeveloping) one or more diseases, disorders, or conditions caused by, orassociated with, aberrant (e.g., insufficient) neurogenesis oraccelerated neuron cell death in a subject in need thereof are featured.The methods include administering to the subject an effective amount ofa compound of formula (I) (and/or a compound of any of the otherformulae described herein) or a salt (e.g., a pharmaceuticallyacceptable salt) thereof as defined anywhere herein to the subject.

In another aspect, the use of a compound of formula (I) (and/or acompound of any of the other formulae described herein) or a salt (e.g.,a pharmaceutically acceptable salt) thereof as defined anywhere hereinin the preparation of, or for use as, a medicament for the treatment(e.g., controlling, relieving, ameliorating, alleviating, or slowing theprogression of) or prevention (e.g., delaying the onset of or reducingthe risk of developing) of one or more diseases, disorders, orconditions caused by, or associated with, aberrant (e.g., insufficient)neurogenesis or exacerbated neuronal cell death is featured.

In embodiments, the one or more diseases, disorders, or conditions caninclude neuropathies, nerve trauma, and neurodegenerative diseases. Inembodiments, the one or more diseases, disorders, or conditions can bediseases, disorders, or conditions caused by, or associated withaberrant (e.g., insufficient) neurogenesis (e.g., aberrant hippocampalneurogenesis as is believed to occur in neuropsychiatric diseases) oraccelerated death of existing neurons. Examples of the one or moreneuropsychiatric and neurodegenerative diseases include, but are notlimited to, schizophrenia, major depression, bipolar disorder, normalaging, epilepsy, traumatic brain injury, post-traumatic stress disorder,Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellarataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke,radiation therapy, chronic stress, and abuse of neuro-active drugs, suchas alcohol, opiates, methamphetamine, phencyclidine, and cocaine. Theresultant promotion of neurogenesis or survival of existing neurons(i.e. a resultant promotion of survival, growth, development, functionand/or generation of neurons) may be detected directly, indirectly orinferentially from an improvement in, or an amelioration of one or moresymptoms of the disease or disorder caused by or associated withaberrant neurogenesis or survival of existing neurons. Suitable assayswhich directly or indirectly detect neural survival, growth,development, function and/or generation are known in the art, includingaxon regeneration in rat models (e.g. Park et al., Science. 2008 Nov. 7;322:963-6), nerve regeneration in a rabbit facial nerve injury models(e.g. Zhang et al., J Transl Med. 2008 Nov. 5; 6(1):67); sciatic nerveregeneration in rat models (e.g. Sun et al., Cell Mol. Neurobiol. 2008Nov. 6); protection against motor neuron degeneration in mice (e.g.Poesen et al. J. Neurosci. 2008 Oct. 15; 28(42):10451-9); rat model ofAlzheimer's disease, (e.g. Xuan et al., Neurosci Lett. 2008 Aug. 8;440(3):331-5); animal models of depression (e.g. Schmidt et al., e.g.Behav Pharmacol. 2007 September; 18(5-6):391-418; Krishnan et al. Nature2008, 455, 894-902); and/or exemplified herein.

Administration

The compounds and compositions described herein can, for example, beadministered orally, parenterally (e.g., subcutaneously,intracutaneously, intravenously, intramuscularly, intraarticularly,intraarterially, intrasynovially, intrasternally, intrathecally,intralesionally and by intracranial injection or infusion techniques),by inhalation spray, topically, rectally, nasally, buccally, vaginally,via an implanted reservoir, by injection, subdermally,intraperitoneally, transmucosally, or in an ophthalmic preparation, witha dosage ranging from about 0.01 mg/kg to about 1000 mg/kg, (e.g., fromabout 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg, fromabout 1 to about 100 mg/kg, from about 1 to about 10 mg/kg) every 4 to120 hours, or according to the requirements of the particular drug. Theinterrelationship of dosages for animals and humans (based on milligramsper meter squared of body surface) is described by Freireich et al.,Cancer Chemother. Rep. 50, 219 (1966). Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537(1970). In certain embodiments, the compositions are administered byoral administration or administration by injection. The methods hereincontemplate administration of an effective amount of compound orcompound composition to achieve the desired or stated effect. Typically,the pharmaceutical compositions of this invention will be administeredfrom about 1 to about 6 times per day or alternatively, as a continuousinfusion. Such administration can be used as a chronic or acute therapy.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

In some embodiments, the compounds described herein can becoadministered with one or more other therapeutic agents. In certainembodiments, the additional agents may be administered separately, aspart of a multiple dose regimen, from the compounds of this invention(e.g., sequentially, e.g., on different overlapping schedules with theadministration of one or more compounds of formula (I) (including anysubgenera or specific compounds thereof)). In other embodiments, theseagents may be part of a single dosage form, mixed together with thecompounds of this invention in a single composition. In still anotherembodiment, these agents can be given as a separate dose that isadministered at about the same time that one or more compounds offormula (I) (including any subgenera or specific compounds thereof) areadministered (e.g., simultaneously with the administration of one ormore compounds of formula (I) (including any subgenera or specificcompounds thereof)). When the compositions of this invention include acombination of a compound of the formulae described herein and one ormore additional therapeutic or prophylactic agents, both the compoundand the additional agent can be present at dosage levels of betweenabout 1 to 100%, and more preferably between about 5 to 95% of thedosage normally administered in a monotherapy regimen.

The compositions of this invention may contain any conventionalnon-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.In some cases, the pH of the formulation may be adjusted withpharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form.

The compositions may be in the form of a sterile injectable preparation,for example, as a sterile injectable aqueous or oleaginous suspension.This suspension may be formulated according to techniques known in theart using suitable dispersing or wetting agents (such as, for example,Tween 80) and suspending agents. The sterile injectable preparation mayalso be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant,or carboxymethyl cellulose or similar dispersing agents which arecommonly used in the formulation of pharmaceutically acceptable dosageforms such as emulsions and or suspensions. Other commonly usedsurfactants such as Tweens or Spans and/or other similar emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

The compositions of this invention may be orally administered in anyorally acceptable dosage form including, but not limited to, capsules,tablets, emulsions and aqueous suspensions, dispersions and solutions.In the case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried corn starch. Whenaqueous suspensions and/or emulsions are administered orally, the activeingredient may be suspended or dissolved in an oily phase is combinedwith emulsifying and/or suspending agents. If desired, certainsweetening and/or flavoring and/or coloring agents may be added.

The compositions of this invention may also be administered in the formof suppositories for rectal administration. These compositions can beprepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

Topical administration of the compositions of this invention is usefulwhen the desired treatment involves areas or organs readily accessibleby topical application. For application topically to the skin, thecomposition should be formulated with a suitable ointment containing theactive components suspended or dissolved in a carrier. Carriers fortopical administration of the compounds of this invention include, butare not limited to, mineral oil, liquid petroleum, white petroleum,propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifyingwax and water. Alternatively, the composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier with suitable emulsifying agents. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water. The compositions of thisinvention may also be topically applied to the lower intestinal tract byrectal suppository formulation or in a suitable enema formulation.

In some embodiments, topical administration of the compounds andcompositions described herein may be presented in the form of anaerosol, a semi-solid pharmaceutical composition, a powder, or asolution. By the term “a semi-solid composition” is meant an ointment,cream, salve, jelly, or other pharmaceutical composition ofsubstantially similar consistency suitable for application to the skin.Examples of semi-solid compositions are given in Chapter 17 of TheTheory and Practice of Industrial Pharmacy, Lachman, Lieberman andKanig, published by Lea and Febiger (1970) and in Remington'sPharmaceutical Sciences, 21st Edition (2005) published by MackPublishing Company, which is incorporated herein by reference in itsentirety.

Topically-transdermal patches are also included in this invention. Alsowithin the invention is a patch to deliver active chemotherapeuticcombinations herein. A patch includes a material layer (e.g., polymeric,cloth, gauze, bandage) and the compound of the formulae herein asdelineated herein. One side of the material layer can have a protectivelayer adhered to it to resist passage of the compounds or compositions.The patch can additionally include an adhesive to hold the patch inplace on a subject. An adhesive is a composition, including those ofeither natural or synthetic origin, that when contacted with the skin ofa subject, temporarily adheres to the skin. It can be water resistant.The adhesive can be placed on the patch to hold it in contact with theskin of the subject for an extended period of time. The adhesive can bemade of a tackiness, or adhesive strength, such that it holds the devicein place subject to incidental contact, however, upon an affirmative act(e.g., ripping, peeling, or other intentional removal) the adhesivegives way to the external pressure placed on the device or the adhesiveitself, and allows for breaking of the adhesion contact. The adhesivecan be pressure sensitive, that is, it can allow for positioning of theadhesive (and the device to be adhered to the skin) against the skin bythe application of pressure (e.g., pushing, rubbing) on the adhesive ordevice.

The compositions of this invention may be administered by nasal aerosolor inhalation. Such compositions are prepared according to techniqueswell-known in the art of pharmaceutical formulation and may be preparedas solutions in saline, employing benzyl alcohol or other suitablepreservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

A composition having the compound of the formulae herein and anadditional agent (e.g., a therapeutic agent) can be administered usingany of the routes of administration described herein. In someembodiments, a composition having the compound of the formulae hereinand an additional agent (e.g., a therapeutic agent) can be administeredusing an implantable device. Implantable devices and related technologyare known in the art and are useful as delivery systems where acontinuous, or timed-release delivery of compounds or compositionsdelineated herein is desired. Additionally, the implantable devicedelivery system is useful for targeting specific points of compound orcomposition delivery (e.g., localized sites, organs). Negrin et al.,Biomaterials, 22(6):563 (2001). Timed-release technology involvingalternate delivery methods can also be used in this invention. Forexample, timed-release formulations based on polymer technologies,sustained-release techniques and encapsulation techniques (e.g.,polymeric, liposomal) can also be used for delivery of the compounds andcompositions delineated herein.

The invention will be further described in the following examples. Itshould be understood that these examples are for illustrative purposesonly and are not to be construed as limiting this invention in anymanner.

EXAMPLES Example 1a and 1b S- andR-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol

Representative Procedure 1 Step 1. Synthesis of3,6-Dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (Epoxide 2-A)

Following a literature procedure (Asso, V.; Ghilardi, E.; Bertini, S.;Digiacomo, M.; Granchi, C.; Minutolo, F.; Rapposelli, S.; Bortolato, A.;Moro, S. Macchia, M. ChemMedChem, 2008, 3, 1530-1534) powdered KOH(0.103 g, 1.85 mmol) was added to a solution of 3,6-dibromocarbazole(0.500 g, 1.54 mmol) in DMF (1.5 mL) at ambient temperature and stirredfor 30 min until dissolved. Epibromohydrin (0.32 mL, 3.8 mmol) was addedvia syringe and the reaction was stirred at room temperature overnight.Upon completion, the solution was partitioned between EtOAc and H₂O. Theaqueous layer was washed 3× with EtOAc, and the combined organics werewashed with saturated aqueous NaCl, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude residue was recrystallized fromEtOAc/Hexane to afford the desired product (389 mg, 66%).

¹H NMR (CDCl₃, 500 MHz) δ 8.10 (d, 2H, J=2.0 Hz), 7.54 (dd, 2H, J=2.0,8.5 Hz), 7.31 (d, 2H, J=8.5 Hz), 4.62 (dd, 1H, J=2.5, 16.0 Hz), 4.25(dd, 1H, J=5.5, 16.0 Hz), 3.29 (m, 1H), 2.79 (dd, 1H, J=4.0, 4.5 Hz),2.46 (dd, 1H, J=2.5, 5.0 Hz).

ESI m/z 381.0 ([M+H]⁺, C₁₅H₁₂Br₂NO requires 379.9)

Representative Procedure 2 Step 2. Synthesis of1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol

Following a literature procedure (Asso, V.; Ghilardi, E.; Bertini, S.;Digiacomo, M.; Granchi, C.; Minutolo, F.; Rapposelli, S.; Bortolato, A.;Moro, S. Macchia, M. ChemMedChem, 2008, 3, 1530-1534) m-Anisidine (1.0mL, 8.95 mmol) was added to a suspension of epoxide 2-A (3.02 g, 7.92mmol) in cyclohexane (73 mL). BiCl₃ (0.657 g, 2.08 mmol) was added andthe mixture was heated to reflux overnight. Upon completion, thereaction was partitioned between EtOAc and H₂O. The aqueous layer waswashed 3× with EtOAc, and the combined organics were washed withsaturated aqueous NaCl, dried over Na₂SO₄, filtered, and concentrated invacuo. The crude residue was purified by chromatography (SiO₂, 0-50%EtOAc/Hexane) to afford the desired alcohol as an opaque yellow solid(998 mg, 25%).

¹H NMR (CDCl₃, 400 MHz) δ 8.12 (d, 2H, J=1.6 Hz), 7.52 (dd, 2H, J=2.0,8.8 Hz), 7.32 (d, 2H, J=8.8 Hz), 7.07 (dd, 1H, J=8.0 Hz), 6.31 (dd, 1H,J=2.4, 8.0 Hz), 6.21 (dd, 1H, J=2.0, 8.0 Hz), 6.12 (dd, 1H, J=2.0, 2.4Hz), 4.34-4.39 (m, 3H), 4.00 (br s, 1H), 3.71 (s, 3H), 3.30 (dd, 1H,J=3.6, 13.2 Hz), 3.16 (dd, 1H, J=6.4, 13.2 Hz), 2.16 (br s, 1H).

¹³C NMR (CDCl₃, 100 MHz) δ 161.0, 149.2, 139.9 (2C), 130.4 (2C), 129.5(2C), 123.8 (2C), 123.5 (2C), 112.8, 111.0 (2C), 106.7, 103.8, 99.8,69.5, 55.3, 48.0, 47.4

ESI m/z 502.9 ([M+H]⁺, C₂₂H₂₁Br₂N₂O₂ requires 503.0)

Step 3. Synthesis of1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-yl3,3,3-trifluoro-2-methoxy-2-phenylpropanoate

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol(0.150 g, 0.298 mmol) was dissolved in anhydrous dichloromethane (6 mL)and cooled to 0° C. Pyridine (0.053 mL, 0.655 mmol) was added, followedby S-(+)-α-methoxy-α-trifluoromethylphenylacetyl chloride (S-Mosher'sacid chloride, 0.083 mL, 0.446 mmol) and dimethylaminopyridine (0.004 g,0.030 mmol). The reaction was allowed to warm to room temperature over 4hours, after which it was quenched by addition of saturated aqueousNaHCO₃. The mixture was extracted 3× with EtOAc, and the combinedorganics were washed with saturated aqueous NaCl, dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude residue was purified bychromatography (SiO₂, O-50% EtOAc/Hexane) to afford a mixture of bothpossible esters and both possible amides (˜5:1 ester:amide ratio by ¹HNMR, 132 mg, 64%). Separation of the mixture was achieved using HPLC(Phenomenex SiO₂ Luna, 21×250 mm, 15% EtOAc/Hexane, 16 mL/min; HPLCRetention time: 25.6 min (ester 1) and 41.2 min (ester 2).

Ester 1: ¹H NMR (CDCl₃, 500 MHz) δ 8.11 (d, 2H, J=2.0 Hz), 7.45 (dd, 2H,J=8.5 Hz), 7.24 (m, 2H), 7.22 (m, 4H), 7.05 (t, 1H, J=8.0 Hz), 6.32 (dd,1H, J=2.0, 8.0 Hz), 6.12 (dd, 1H, J=2.0, 8.0 Hz), 6.05 (dd, 1H, J=2.0,2.5 Hz), 5.59 (m, 1H), 4.54 (d, 2H, J=6.5 Hz), 3.71 (br s, 1H), 3.69 (s,3H), 3.43 (m, 1H), 3.29 (ddd, 1H, J=5.5, 13.5 Hz), 3.19 (s, 3H).

Ester 2: ¹H NMR (CDCl₃, 500 MHz) δ 8.08 (d, 2H, J=2.0 Hz), 7.42 (dd, 2H,J=2.0, 9.0 Hz), 7.28 (m, 2H), 7.24 (m, 4H), 7.04 (t, 1H, J=8.0 Hz), 6.31(dd, 1H, J=2.0, 8.5 Hz), 6.11 (dd, 1H, J=2.0, 8.0 Hz), 6.01 (dd, 1H,J=2.0, 2.5 Hz), 5.63 (m, 1H), 4.49 (d, 2H, J=6.5 Hz), 3.82 (dd, 1H,J=5.5, 6.0 Hz), 3.66 (s, 3H), 3.42 (s, 3H), 3.39 (m, 1H), 3.28 (dd, 1H,J=5.0, 13.5 Hz)

Step 4. Synthesis of S- andR-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol

Following a literature procedure (Abad, J-L.; Casas, J.; Sanchez-Baeza,F.; Messeguer, A. J. org. Chem. 1995, 60, 3648-3656) ester 1 fromexample 3 (0.011 g, 0.015 mmol) was dissolved in degassed Et₂O (0.150mL) and cooled to 0° C. Lithium aluminum hydride (1M in THF, 0.018 mL,0.018 mmol) was added via syringe and the reaction was stirred for 20min. Upon completion by TLC the reaction was quenched by the addition ofMeOH and stirred for 45 min. The mixture was partitioned between EtOAcand H₂O. The aqueous layer was extracted 3× with EtOAc, and the combinedorganics were washed with saturated aqueous NaCl, dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude residue was purified bychromatography (SiO₂, O-30% EtOAc/Hexane) to afford the desired alcohol(4.7 mg, 64%).(From Ester 1):[α]_(D)=+10°(c=0.1,CH₂Cl₂);  Example 1a(From Ester 2):[α]_(D)=−14°(c=0.1,CH₂Cl₂);  Example 1b

Example 21-(3,6-dibromo-9H-carbazol-9-yl)-3-(2-iminopyridin-1(2H)-yl)propan-2-ol

Example 2 was prepared following Representative Procedure 2, except witha reaction time of 2 days at 80° C. The crude product was used withoutfurther purification.

¹H NMR (CDCl₃, 400 MHz) δ=8.14 (2H, J=1.9 Hz), 7.55 (dd, 2H, J=1.9, 8.8Hz), 7.35 (d, 2H, J=8.7 Hz), 6.83 (t, 1H, J=7.6 Hz), 6.37 (d, 1H,J=6.8), 6.32 (d, 1H, J=9.1 Hz), 5.65 (t, 1H, J=6.7 Hz), 4.39 (dm, 5H),3.54 (d, 1H, J=13.9 Hz)

MS (ESI), m/z: found 473.9 (M+1)⁺ ([M+1]+ for C₂₀H₁₈Br₂N₃O requires474.0)

Example 3a 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylthio)propan-2-ol

Benzenethiol (30 Tl, 0.29 mmol) was added to a solution of3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (epoxide 2-A, 101.6 mg,0.27 mmol) in 5.0 ml MeOH at r.t. The reaction mixture was heated to 80°C. and stirred overnight at the same temperature. The reaction wasmonitored by 1c/ms for the consumption of SM. The reaction was cooled,diluted with ethyl acetate and washed with water and brine. The organiclayer was dried over Na₂SO₄, filtered and condensed.

¹H NMR (CDCl₃, 400 MHz) Λ 8.03 (d, 2H, J=2.1 Hz), 7.48 (dd, 2H, J=2.0,8.7 Hz), 7.33-7.20 (m, 7H), 4.33 (dd, 1H, J=4.3, 14.9 Hz), 4.20 (dd, 1H,J=6.9, 14.9 Hz), 4.00-4.12 (m, 1H), 3.05 (dd, 1H, J=5.3, 13.9 Hz), 2.93(dd, 1H, J=7.2, 13.9 Hz), 2.51 (bs, 1H);

¹³C NMR (CDCl₃, 126 MHz) δ 139.9, 134.5, 130.4, 129.6, 129.4, 127.4,123.8, 123.4, 112.7, 111.1, 69.3, 48.1, 39.4;

MS (ESI), m/z: found: 505.9 [M+O−1]⁻ ([M+O−1]— for C₂₁H₁₇Br₂NOS requires504.9; (oxidation occurred under MS conditions; NMR not consistent withsulfoxide)

Example 3b 1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol

Following Representative Procedure 1, the title compound of Example 3bwas prepared from dibromocarbazole and phenoxymethyloxirane in 61%yield.

¹H NMR (CDCl₃, 400 MHz) δ 8.14 (d, 2H, J=1.9 Hz), 7.51 (dd, 2H, J=1.9,8.7 Hz), 7.36 (d, 2H, J=8.8 Hz), 7.127-7.32 (m, 2H), 7.00 (t, 1H, J=7.3Hz), 6.87 (dd, 2H, J=0.8, 8.9 Hz), 4.58 (dd, 1H, J=7.9, 16.7 Hz),4.41-4.49 (m, 2H), 4.00 (dd, 1H, J-4.4, 9.6 Hz), 3.89 (dd, 1H, J=4.5,9.5 Hz), 2.38 (d=1H, J=5.7 Hz)

MS (ESI), m/z: 517.9 [M+HCOO]⁻ ([M+HCOO]— for C21H17Br2NO2 requires518.0

Example 3c1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfinyl)propan-2-ol

An aqueous solution of NaIO₄ (5.14 g) was added to silica gel (20 g) andshaken until a free-flowing solid was obtained. Thio-ether(1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylthio)propan-2-ol, (0.0120 g,0.0244 mmol) and NaIO₄/silica gel (0.1018 g NaIO4, 0.122 mmol) weresuspended in CH₂Cl₂ (1 mL). The white suspension was heated to 50° C. ina sealed vial for 4 hours until TLC showed complete disappearance ofstarting material. The reaction mixture was subjected to silica gelchromatography using Hexanes/EtOAc (1:9) to afford 0.0081 g white solidas product, yield 65.4% as a 1:1 mixture of diastereomers.

¹H NMR (CDCl₃, 400 MHz) δ ppm=2.39 (dd, J=13.7, 1.7 Hz, 1H diastereomerA) 2.83 (dd, J=13.2, 2.9 Hz, 1 Dias. B) 2.97 (dd, J=13.2, 8.6 Hz, 1HDiast. B) 3.15 (dd, J=13.7, 9.3 Hz, 1H Diast. A) 3.90 (d, J=1.7 Hz, 1HDias. B) 3.96 (d, J=2.6 Hz, 1H Diast. A), 4.24 (dd, J=15.0, 6.3 Hz, 1HDias A), 4.30 (dd, J=15.2, 6.7, 1H Diast. B), 4.35 (dd, J=15.2, 6.0 Hz,1H Diast. B), 4.45 (dd, J=15.1, 6.4 Hz, 1H Diast. B), 4.65-4.55 (m, 1HDiast. A) 4.87-4.76 (m, 1H Diast. B) 7.16 (d, J=8.7 Hz, 2H Diast. A)7.34 (d, J=8.8 Hz, 2H Diast B) 7.60-7.30 (m, 7H Diast A+7H Dast. B) 8.08(d, J=1.9 Hz, 2H Diast. A) 8.13 (d, J=1.9 Hz, 2H Diast B)

MS (ESI) m/z: 549.9 [M+HCOO]⁻ ([M+CHOO]— for C₂₁H₁₇Br₂NO₂S requires549.9).

Example 3d1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol

To a solution of thio-ether(1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylthio)propan-2-ol, (0.0113 g,0.0230 mmol) in 0.5 mL CH₂Cl₂, a solution of mCPBA (ca. 77% pure, 0.0129g, 0.0575 mmol) in 0.5 mL CH₂Cl₂ was added dropwise. The mixture wasstirred at room temperature overnight. The crude reaction mixture wasneutralized by 9 mL Et₃N and stirred for 30 min then diluted with 30 mLEtOAc and washed with saturated NaHCO₃ 3×30 mL and brine 1×30 mL. Theorganic layer was dried over anhydrous Na₂SO₄ and evaporated to affordthe crude product, which was subjected to silica gel chromatographyusing Hexanes/EtOAc (3:7) to afford white solid as product (0.0120 g,yield 99.7%).

¹H NMR (CDCl₃, 400 MHz) ppm 3.15 (dd, J=14.2, 3.0 Hz, 1H) 3.21-3.31 (m,2H) 4.38 (d, J=6.3 Hz, 2H) 4.60-4.76 (m, 1H) 7.25-7.31 (m, 2H) 7.47-7.56(m, 4H) 7.60-7.70 (m, 1H) 7.79 (dd, J=8.4, 1.2 Hz, 2H) 8.11 (d, J=1.9Hz, 2H); MS (ESI) m/z: 565.9 [M+HCOO]; 543.7 [M+Na]⁺ ([M+HCOO]⁻ forC21H17Br2NO3S requires 595.9; [M+Na]+ requires 543.9).

Example 4N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)acetamide

Following a literature procedure (Morcuende, A.; ors, M.; Valverde, S.;Herradón, B. J. Org. Chem. 1996, 5264-5270) triethylamine (14 Tl, 0.10mmol) and acetyl chloride (8 Tl, 0.11 mmol) were added to aheterogeneous mixture of1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (53mg, 0.11 mmol) and dibutyltin oxide (5.5 mg, 0.022 mmol) in anhydroustoluene (1.5 ml). The reaction vessel was purged with nitrogen, sealedand heated under microwave radiation to 150° C. for 9 minutes. Thereaction was monitored by 1c/ms and all SM had been consumed. Theheterogeneous solution was filtered under vacuum to yield a white solid.The crude product was used without purification.

¹H NMR (CDCl₃, 500 MHz) Λ 8.09 (2H, J=1.6 Hz), 7.52 (dd, 2H, J=1.8, 8.7Hz), 7.29 (d, 2H, J=8.8 Hz), 7.26 (t, 1H, J=8.2 Hz), 6.86 (dd, 1H,J=2.5, 8.4 Hz), 6.68 (dd, 1H, J=1.3, 7.7 Hz), 6.62 (s, 1H,), 4.33-4.40(m, 1H), 4.29 (dd, 2H, J=2.6, 6.0 Hz), 3.94 (d, 1H, J=4.1 Hz), 3.76 (s,3H), 3.51 (dd, 1H, J=2.3, 14.0 Hz), 1.9 (s, 3H);

¹³C NMR (CDCl₃, 126 MHz) δ 173.6, 160.9, 144.5, 139.9, 131.0, 129.4,123.8, 123.4, 119.7, 113.9, 113.5, 112.6, 111.1, 70.9, 55.7, 55.2, 46.0,22.8.

MS (ESI), m/z: 544.9 (M+1)⁺ ([M+1]⁺ for C₂₄H₂₂Br₂N₂O₃ requires 545.0)

Example 55-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(3-methoxyphenyl)-oxazolidin-2-one

Methyl chloroformate (10 Tl, 0.13 mmol) was added to a stirring solutionof jn-128-186 (55.0 mg, 0.11 mmol) and indium powder (3.5 mg, 0.030mmol) in acetonitrile (3.0 ml), and the reaction mixture was stirredovernight at r.t. An additional 3.1 mg (0.027 mmol) of indium and 20 Tl(2.6 eq.) of methyl chloroformate were added. After several hours, thereaction was diluted with ethyl acetate, and washed with water and thenbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The methyl carbonate was purified via flash chromatographyin 20-40% ethyl acetate/hexanes. Sodium methoxide (3.0 ml) was added toa solution of carbonate (21.3 mg, 0.038 mmol) and methanol (1.0 ml).After an hour at ambient temperature the solution was diluted with waterand extracted with ethyl acetate. The organic layer was washed withwater and brine and condensed.

¹H NMR (CD₃COCD₃, 500 MHz) Λ 8.40 (s, 2H), 7.78 (d, 2H, J=8.5 Hz), 7.64(d, 2H, J=8.9 Hz), 7.23-7.28 (m, 2H), 7.05 (d, 1H, J=8.3 Hz), 6.70 (d,1H, J=8.3 Hz), 5.24-5.31 (m, 1H), 5.00 (dd, 1H, J=7.9, 15.7 Hz), 4.91(dd, 1H, J=3.2, 15.8 Hz), 4.38 (t, 1H, J=9.3 Hz), 4.05 (m, 1H), 3.78 (s,3H);

¹³C NMR (CDCl₃, 126 MHz) δ 160.4, 153.9, 140.3, 140.2, 129.8, 129.4,124.0, 123.5, 112.4, 112.1, 110.3, 109.0, 104.4, 71.9, 54.9, 47.9, 46.6.

MS (ESI), m/z: 528.9 (M+1)⁺′. ([M+1]+ for C₂₃H₁₉Br₂N₂O₃ calculated529.0)

Example 6aN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline

Representative Procedure 3: Epoxide Opening with Ns-Protected AnilinesN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamide

A heterogeneous mixture of N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide(100.2 mg, 0.32 mmol) in toluene (2.5 ml, 0.13 M) under a N₂ atmospherewas cooled in a dry ice/acetone bath before dropwise addition ofn-butyllithium (200 ul of 1.78 M in hexanes, 0.36 mmol). The reactionwas stirred at −78° C. for 10 minutes before addition of carbazoleepoxide 2-A. The heterogeneous mixture was stirred at room temperaturefor 5 minutes before heating at 100° C. for 48 hours. The cooledreaction was diluted with EtOAc and washed three times with 5% aceticacid solution, followed by a brine wash. The organic layer was driedover Na₂SO₄, filtered and condensed. The crude mixture was purified in100% dichloromethane. Yield=88%

¹H NMR (CDCl₃, 400 MHz) δ 8.23 (d, 2H, J=8.5 Hz), 8.06 (d, 2H, J=1.9Hz), 7.65 (d, 2H, J=8.5 Hz), 7.46, (dd, 2H, J=8.6, 1.9 Hz), 7.22 (d, 2H,J=8.8 Hz), 6.94 (d, 2H, 8.8 Hz), 6.83 (d, 2H, 9.1 Hz), 4.44 (dd, 1H,J=14.9, 3.6 Hz), 4.26-4.34 (m, 1H), 4.17-4.24 (bs, 1H), 3.81 (s, 3H),3.62-3.75 (m, 2H).

MS (ESI), m/z: 732.0 [(M+HCOO⁻); C₂₈H₂₃Br₂N₃O₆S (M) requires 687]

Representative Procedure 4: Fluorination of Secondary AlcoholN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamide

An oven dried 20 ml scintillation vial containingN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamide(18.3 mg, 0.027 mmol; see representative procedure 3 above) was purgedwith N₂ and charged with anhydrous dichloromethane (1.5 ml, 0.018 M).The sealed vial was cooled in a dry ice acetone bath before the dropwiseaddition of diethylaminosulfur trifluoride (DAST, 7 ul, 0.053 mmol). Thereaction temperature was maintained at −78° C. for an hour and thenslowly warmed to room temperature and stirred overnight. The reactionwas quenched with 2.0 ml of saturated NaHCO₃ solution and diluted with 6ml CH₂Cl₂ and extracted three times. The combined organics were driedover Na₂SO₄, filtered and condensed. Crude product carried forward.Quantitative yield.

Alternatively, morpholinosulfur trifluoride (MORPHO-DAST) can be used atrt.

¹H NMR (CDCl₃, 400 MHz) δ 8.28 (d, 2H, J=8.0 Hz), 8.13 (s, 2H), 7.72 (d,2H, J=8.7 Hz), 7.54, (d, 2H, J=8.0 Hz), 7.21 (d, 3H, J=8.1 Hz), 6.89(dd, 1H, 8.3, 2.4 Hz), 6.67 (t, 1H, J=2.0 Hz), 6.55 (d, 1H, J=8.0 Hz)4.93 (m, 1H), 4.43-4.68 (m, 2H), 4.20 (t, 1H, J=6.2 Hz), 3.81-3.99 (m,2H), 3.75 (s, 3H).

MS (ESI), m/z: calculated 688.96. found 733.9 (M+HCOO⁻).

Representative Procedure 5: Nosyl Group Deprotection (See Fukuyama, T.;Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373-6374)N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline

To a vial containingN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamide(21.0 mg, 0.030 mmol; see representative procedure 4) was added lithiumhydroxide (3.2 mg, 0.134 mmol), dimethylformamide (0.5 ml, 0.06 M) andmercaptoacetic acid (4.2 ul 0.060 mmol). After stirring at rt for 1 hthe reaction mixture was diluted with EtOAc and washed sequentially withwater, saturated sodium bicarbonate solution, water (3×) and brine. Theorganic layer was dried over Na₂SO₄, filtered and condensed. The crudereaction mixture was purified in 30% EtOAc/hexanes (+0.2% TEA), with13.6 mg isolated. Yield=88%

Additional Representative Procedure

DAST [(Et₂NSF₃) 0.12 ml, 0.916 mmol] was added dropwise to a solution of1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol(0.102 g, 0.203 mmol) in 6.0 ml of anhydrous DCM at −78° C. The reactionwas stirred at −78° C. for one hour before being slowly warmed to 0° C.over 5 hours. The reaction was quenched by addition of phosphate buffer(pH=8) and extracted with DCM. The aqueous phase was extracted twicewith 10 ml DCM. The combined organics were dried over Na₂SO4, filteredand concentrated. The crude reaction material was purified by flashchromatography on SiO2 (20% EtOAc/hexanes/0.2% TEA). Fractionscontaining the desired fluorinated product were further purified with40% EtOAc/hexanes (+0.1% TEA). Isolated 5.7 mg desired product.

Analytical Data for the Title Compound of Example 6a

¹H NMR (CDCl₃, 500 MHz) A 8.16 (2H, J=2.0 Hz), 7.56 (dd, 2H, J=1.9, 8.7Hz), 7.31 (d, 2H, J=8.6 Hz), 7.11 (t, 1H, J=8.1 Hz), 6.36 (dd, 1H,J=2.2, 8.1 Hz), 6.23 (dd, 1H, J=2.0, 8.0 Hz), 6.15 (t, 1H, J=2.3 Hz),5.11 (dddd, 1H, J=4.6, 5.8, 10.4, 47.7 Hz), 4.60 (m, 2H), 4.39 (dm, 2H),3.95 (t, 1H, J=6.3 Hz), 3.75 (s, 3H)

MS (ESI), m/z: 504.9 (M+1)⁺. ([M+1]+ for C₂₂H₁₉Br₂FN₂O calculated 505.0)

Example 6bN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxy-N-methylaniline

The title compound of Example 6b was prepared according to the proceduredescribed in Representative Procedure 4 except using1-(3,6-dibromo-9H-carbazol-9-yl)-3-((3-methoxyphenyl)(methyl)-amino)propan-2-ol(see Example 23)

¹H NMR (CDCl₃, 500 MHz) δ 8.13 (d, 2H, J=1.9 Hz), 7.54 (dd, 2H, J=1.9,8.8 Hz), 7.23 (d, 2H, J=8.7 Hz), 7.12 (t, 1H, J=8.2 Hz), 6.32 (dd, 1H,J=2.2, 8.1 Hz), 6.26 (dd, 1H, J=2.3, 8.0 Hz), 6.17 (t, 1H, J=2.4 Hz),5.10 (dddd, 1H, J=4.6, 6.4, 10.7, 48.5 Hz), 4.37-4.48 (m, 2H), 3.72 (s,3H), 3.60-3.71 (m, 1H), 3.53 (td, 1H, J=6.9, 15.9 Hz), 2.99 (s, 3H).

MS (ESI), m/z: 518.9 [M+1]⁺ ([M+H]+ for C23H21Br2FN2O requires 519.0.)

Example 7a1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-one

Trietheylamine (1.65 ml, 11.8 mmol) was added to a stirring solution of1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol(1.02 g, 2.02 mmol) in DMSO (21 ml). The solution was stirred for 30minutes before addition of sulfur trioxide pyridine complex (0.659 g,4.14 mmol). After stirring overnight, additional triethylamine (1.0 ml,7.17 mmol) was added, followed by sulfur trioxide pyridine complex(0.663 mg, 4.17 mmol) an hour later. After stirring for 1 h, the orangesolution was diluted with ˜150 ml ethyl acetate and washed several timeswith water and then brine. The organic layer was dried over Na₂SO₄,filtered and concentrated to yield brown foam. Flash chromatography onSiO₂ 100% (CH₂Cl₂+0.2% TEA) provided a higher R_(f) ketone (thioether,18%) and a lower R_(f) ketone (Yield=40%).

Major product: ¹H NMR (CDCl₃, 400 MHz) δ 8.18 (2H, J=1.9 Hz), 7.56 (dd,2H, J=1.9, 8.7 Hz), 7.11 (d, 2H, J=8.8 Hz), 7.06 (t, 1H, J=8.1 Hz), 6.30(dd, 1H, J=2.3, 8.2 Hz), 6.07 (dd, 1H, J=2.0, 8.0 Hz), 6.11 (t, 1H,J=2.2 Hz), 5.08 (s, 2H), 4.41 (t, 1H, J=4.8 Hz), 3.90 (d, 2H, J=5.1 Hz),3.72 (s, 3H)

¹³C NMR (CDCl₃, 126 MHz) δ=202.9, 161.1, 147.9 (2C), 139.5, 130.6 (2C),129.9 (2C), 124.1 (2C), 123.9 (2C), 113.5, 110.1 (2C), 103.7, 99.3,55.4, 51.9, 51.0.

MS (ESI), m/z: 500.9 (M+1)⁺ ([M+1]+ for C₂₂H₁₈Br₂N₂O₂ requires 501.0)

Example 7b3-(3,6-dibromo-9H-carbazol-9-yl)-1-(3-methoxyphenylamino)-1-(methylthio)propan-2-one

The title compound of Example 7b was obtained as a minor product in thepreparation of the title compound of Example 7a.

¹H NMR (CDCl₃, 400 MHz): δ 8.16 (d, 2H, J=2.0 Hz), 7.55 (dd, 2H, J=1.7,8.8 Hz), 7.25 (d, J=8.8 Hz, 2H), 7.12 (t, 1H, J=8.4 Hz), 6.39 (dd, 1H,J=2.2, 8.2 Hz), 6.33 (dd, 1H, J=2.2, 8.0 Hz), 6.29 (t, 1H, J=2.2 Hz),5.50 (d, 1H, J=18.0 Hz), 5.22 (d, 1H, J=18.4 Hz), 5.25 (d, J=8.0 Hz,1H), 4.50 (d, J=8.0 Hz, 1H, exchangeable), 3.76 (s, 3H), 1.74 (s, 3H)

¹³C NMR (CDCl₃, 126 MHz) δ=193.2, 160.9, 143.9 (2C), 139.8 (2C), 130.4,129.8 (2C), 124.1, 123.7 (2C), 113.4 (2C), 110.3 (2C), 107.8, 104.7,101.0, 60.3, 55.4, 48.9, 9.0

ESI m/z 498.9 [M-SMe+H]⁺ ([M-SMe+H]+ for C₂₃H₂₀Br₂N₂O₂S requires 499.0.

HRMS m/z: 546.9675 [M+H]+([M+H]+ for C₂₃H₂₀Br²N₂O₂S requires 545.9612.

Example 8N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-methoxypropyl)-3-methoxyaniline

Sodium hydride (9.0 mg, 0.23 mmol) was added to a stirring solution of1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol(99.3 mg, 0.20 mmol) in DMF 0.5 ml, 0.39 M). The solution was stirred atroom temperature for about 70 minutes before the dropwise addition of asolution of methyl iodide (14 ml. 0.22 mol) in DMF (1.0 ml). Thereaction was monitored by 1c/ms for the consumption of SM and theappearance of O and N-methyl products. After 2.5 hours of stirring atr.t, conversion was about 30% and about 5% N-methyl product had formed.The reaction was stopped when an increase of N-Me to O-Me had beenobserved and conversion was about 50%. The brown solution was dilutedwith ethyl acetate and washed several times with water and finallybrine. The organic layer was dried over Na₂SO₄, filtered and condensed.The mixture was purified by preparative TLC 30% EtOAc/hexanes.

¹H NMR (CDCl₃, 400 MHz) Λ 8.13 (s, 2H), 7.51 (dd, 2H, J=1.8, 8.8 Hz),7.31 (d, 2H, J=8.7 Hz), 7.09 (t, 1H, J=8.2 Hz), 6.33 (dd, 1H, J=2.3, 8.3Hz), 6.21 (dd, 1H, J=2.1, 8.0 Hz), 6.12 (m, 1H), 4.42 (m, 1H), 4.03 (bs,1H), 3.85 (m, 1H), 3.74 (s, 3H), 3.29 (s, 3H), 3.09 (m, 2H)

¹³C NMR (CDCl₃, 126 MHz) δ 161.0, 149.4, 139.8, 130.4, 129.5, 123.8,123.5, 112.7, 110.9, 106.7, 103.6, 99.7, 78.2, 58.3, 55.3, 45.3, 44.3.

MS (ESI), m/z: 516.9 (M+1)⁺ ([M+1]+ for C₂₃H₂₂Br₂N₂O₂ requires 517.0).

Example 91-(3,6-Dimethyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol

Step 1. Synthesis of 3,6-Dimethyl-9-(oxiran-2-ylmethyl)-9H-carbazole

Following Representative Procedure 1,3,6-dimethyl carbazole (Beyer, M.;Fritscher, J.; Feresin, E.; Schiemann, O. J. Org. Chem. 2003, 68,2209-2215) was added to epichlorohydrin in 69% yield.

¹H NMR (CDCl₃, 500 MHz) Λ 7.84 (d, 2H, J=1.0 Hz), 7.30 (d, 2H, J=8.5Hz), 7.26 (dd, 2H, J=1.0, 8.5 Hz), 4.54 (dd, 1H, J=3.5, 16.0 Hz), 4.35(dd, 1H, J=4.5, 16.0 Hz), 3.30 (m, 1H), 2.76 (dd, 1H, J=4.0, 5.0 Hz),2.52 (s, 6H), 2.51 (m, 1H)

Step 2. Synthesis of1-(3,6-Dimethyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol

Following Representative procedure2,1-(3,6-Dimethyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-olwas prepared from 3,6-Dimethyl-9-(oxiran-2-ylmethyl)-9H-carbazole in 22%following purification by preparative TLC.

¹H NMR (CDCl₃, 500 MHz) δ 7.84 (d, 2H, J=0.5 Hz), 7.30 (d, 2H, J=8.0Hz), 7.23 (d, 2H, J=8.0 Hz), 7.05 (t, 1H, J=8.0 Hz), 6.28 (dd, 1H,J=2.5, 8.0 Hz), 6.21 (dd, 1H, J=2.5, 8.0 Hz), 6.12 (dd, 1H, J=2.0, 2.5Hz), 4.39 (m, 3H), 4.01 (br s, 1H), 3.68 (s, 3H), 3.31 (dd, 1H, J=3.0,11.5 Hz), 3.17 (dd, 1H, J=6.5, 13.0 Hz), 2.51 (s, 6H), 2.13 (br s, 1H)

¹³C NMR (CDCl₃, 125 MHz) δ 161.0, 149.5, 139.5 (2C), 130.3 (2C), 128.7,127.3 (2C), 123.2 (2C), 120.5 (2C), 108.7 (2C), 106.7, 103.7, 99.5,69.7, 55.2, 48.0, 47.4, 21.6 (2C).

ESI m/z 375.2 ([M+H]⁺, C₂₄H₂₇N₂O₂ requires 375.2)

Example 101-(3-Bromo-6-methyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol

Step 1. Synthesis of 3-Bromo-6-methyl-9-(oxiran-2-ylmethyl)-9H-carbazole

Following Representative Procedure 2, Example 14 was prepared in 74%yield.

¹H NMR (CDCl₃, 500 MHz) δ 8.13 (d, 1H, J=1.5 Hz), 7.80 (d, 1H, J=1.0Hz), 7.50 (dd, 1H, J=2.0, 8.5 Hz), 7.33-7.28 (m, 3H), 4.57 (dd, 1H,J=3.0, 15.5 Hz), 4.29 (dd, 1H, J=5.0, 15.5 Hz), 3.29 (m, 1H), 2.77 (dd,1H, J=4.0, 4.5 Hz), 2.51 (s, 3H), 2.48 (dd, 1H, J=2.5, 4.5 Hz)

Step 2. Synthesis of1-(3-Bromo-6-methyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol

Following Representative Procedure 2, Example 15 was prepared from3-Bromo-6-methyl-9-(oxiran-2-ylmethyl)-9H-carbazole in 41% yield.

¹H NMR (CDCl₃, 500 MHz) δ 8.14 (d, 1H, J=2.0 Hz), 7.81 (s, 1H), 7.48(dd, 1H, J=2.0, 8.5 Hz), 7.31 (d, 1H, J=5.0 Hz), 7.29 (br s, 1H), 7.06(t, 1H, J=8.5 Hz), 6.29 (dd, 1H, J=2.0, 8.0 Hz), 6.21 (dd, 1H, J=2.0,8.0 Hz), 6.11 (t, 1H, J=2.0 Hz), 4.37 (m, 3H), 3.99 (br s, 1H), 3.70 (s,3H), 3.30 (dd, 1H, J=3.5, 13.5 Hz), 3.16 (dd, 1H, J=6.5, 13.5 Hz), 2.51(s, 3H), 2.14 (br s, 1H)

¹³C NMR (CDCl₃, 125 MHz) δ 161.0, 149.4, 139.8, 139.5, 130.3, 129.4,128.5, 128.2, 124.7, 123.2, 122.3 120.7, 112.1, 110.6, 109.0, 106.7,103.7, 99.6, 69.5, 55.3, 47.9, 47.4, 21.5.

ESI m/z 439.1 ([M+H]⁺, C₂₃H₂₄BrN₂O₂ requires 439.1)

Example 111-(3,6-Dichloro-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol

Step 1. Synthesis of 3,6-Dichloro-9-(oxiran-2-ylmethyl)-9H-carbazole

Following Representative Procedure 1,3,6-Dichloro-9-(oxiran-2-ylmethyl)-9H-carbazole was prepared in 23%yield.

¹H NMR (CDCl₃, 600 MHz) δ 7.92 (d, 2H, J=1.8 Hz), 7.40 (dd, 2H, J=1.8,9.0 Hz), 7.32 (d, 2H, J=9.0 Hz), 4.59 (dd, 1H, J=3.0, 16.2 Hz), 4.22(dd, 1H, J=5.4, 16.2 Hz), 3.27 (m, 1H), 2.78 (dd, 1H, J=4.2, 4.8 Hz),2.46 (dd, 1H, J=2.4, 4.8 Hz)

Step 2. Synthesis of1-(3,6-Dichloro-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol

Following Representative Procedure2,1-(3,6-dichloro-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-olwas prepared from 3,6-Dichloro-9-(oxiran-2-ylmethyl)-9H-carbazole in 37%yield.

¹H NMR (CDCl₃, 500 MHz) δ 7.95 (d, 2H, J=2.0 Hz), 7.38 (dd, 2H, J=2.0,8.5 Hz), 7.33 (d, 2H, J=9.0 Hz), 7.06 (t, 1H, J=8.0 Hz), 6.30 (dd, 1H,J=2.0, 8.0 Hz), 6.20 (dd, 1H, J=2.0, 8.0 Hz), 6.11 (dd, 1H, J=2.0, 2.5Hz), 4.30-4.35 (m, 3H), 3.70 (s, 3H), 3.28 (dd, 1H, J=3.5, 13.0 Hz),3.13 (dd, 1H, J=6.5, 13.0 Hz)

¹³C NMR (CDCl₃, 150 MHz) δ 161.0, 149.3, 139.7, 130.4 (2C), 126.9 (2C),125.5 (2C), 123.4 (2C), 120.4 (2C), 110.5 (2C), 106.7, 103.8, 99.8,69.6, 55.3, 48.0, 47.5.

ESI m/z 415.0 ([M+H]⁺, C₂₂H₂₀Cl₂N₂O₂ requires 415.1)

Example 121-(5-bromo-2,3-dimethyl-1H-indol-1-yl)-3-(phenylamino)propan-2-ol

Step 1. Synthesis of 5-Bromo-2,3-dimethyl-1H-indole

Following a published procedure (Gundersen, E. G. U.S. Patent App. Publ.US 2005/070592) 2-Butanone (0.11 mL, 1.278 mmol) was added to a solutionof 4-bromophenylhydrazine hydrochloride (0.300 g, 1.342 mmol in EtOH(3.8 mL). The mixture was heated to reflux for 22 h, concentrated invacuo, and partitioned between EtOAc and 1N HCl. The organic layer waswashed with H₂O and saturated aqueous NaHCO₃, dried over Na₂SO₄,filtered, and concentrated. The crude residue was purified bychromatography (SiO₂, 0-20% EtOAc/Hexane) to afford the desired indoleas a pink powder (200 mg, 67%).

¹H NMR (CDCl₃, 500 MHz) δ 7.69 (br s, 1H), 7.55 (d, 1H, J=2.0 Hz), 7.15(dd, 1H, J=2.0, 8.5 Hz), 7.09 (dd, 1H, J=0.5, 8.5 Hz), 2.34 (s, 3H),2.15 (d, 3H, J=0.5 Hz)

ESI m/z 224.0 ([M+H]⁺, C₁₀H₁₁BrN requires 224.0)

Step 2. Synthesis of5-Bromo-2,3-dimethyl-1-(oxiran-2-ylmethyl)-1H-indole

Following Representative Procedure1,5-bromo-2,3-dimethyl-1-(oxiran-2-ylmethyl)-1H-indole was prepared from5-Bromo-2,3-dimethyl-1H-indole in 48% yield.

¹H NMR (CDCl₃, 500 MHz) δ 7.58 (d, 1H, J=2.0 Hz), 7.20 (dd, 1H, J=2.0,8.5 Hz), 7.10 (d, 1H, J=8.5 Hz), 4.35 (dd, 1H, J=3.0, 16.0 Hz), 4.09(dd, 1H, J=4.5, 16.0 Hz), 3.17 (m, 1H), 2.72 (t, 1H, J=4.5 Hz), 2.35(dd, 1H, J=3.0, 5.0 Hz), 2.33 (s, 3H), 2.19 (s, 3H).

ESI m/z 280.0 ([M+H]⁺, C₁₃H₁₅BrNO requires 280.0)

Step 3. Synthesis of1-(5-bromo-2,3-dimethyl-1H-indol-1-yl)-3-(phenylamino)propan-2-ol

Following Representative Procedure2,1-(5-bromo-2,3-dimethyl-1H-indol-1-yl)-3-(phenylamino)propan-2-ol wasprepared from 5-Bromo-2,3-dimethyl-1-(oxiran-2-ylmethyl)-1H-indole in39% yield.

¹H NMR (CDCl₃, 500 MHz) δ 7.58 (d, 1H, J=2.0 Hz), 7.17 (dd, 2H, J=7.0,8.5 Hz), 7.11 (d, 1H, J=8.5 Hz), 6.75 (t, 1H, J=7.0 Hz), 6.60 (d, 2H,J=8.5 Hz), 4.17 (m, 1H), 4.15 (m, 2H), 3.27 (dd, 1H, J=3.0, 8.5 Hz),3.12 (dd, 1H, J=7.0, 13.0 Hz), 2.34 (s, 3H), 2.19 (s, 3H)

¹³C NMR (CDCl₃, 125 MHz) δ 147.9, 135.1, 134.3, 130.6, 129.6 (2C),123.6, 120.9, 118.6, 113.7 (2C), 112.5, 110.5, 107.1, 69.9, 47.7, 47.4,10.7, 9.0

ESI m/z 373.0 ([M+H]⁺, C₁₉H₂₂BrN₂O requires 373.1).

Example 131-(3,6-Dibromo-9H-pyrido[3,4-b]indol-9-yl)-3-(phenylamino)propan-2-ol

Step 1. Synthesis of 3,6-Dibromo-β-carboline

Following a literature procedure (Ponce, M. A.; Erra-Balsells, R. J.Heterocyclic Chem. 2001, 38, 1087) 13-Carboline (0.100 g, 0.595 mmol)and SiO₂ (1.00 g) were suspended in CH₂Cl₂ (15 mL). N-Bromosuccinimde(0.212 g, 1.189 mmol) was dissolved in CH₂Cl₂ (15 mL) and the solutionwas added to the carboline mixture slowly via syringe in the absence oflight. The reaction was stirred at ambient temperature for 2.5 h, afterwhich the silica gel was filtered off and washed 3×CH₂Cl₂. The combinedorganic layer was extracted with 0.1 M NaOH and saturated aqueous NaCl,dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by chromatography (SiO₂, 0-100% EtOAc/Hexane) toafford the desired 3,6-dibrominated carboline (25 mg, 13%) as well as6,8-dibrominated carboline (15 mg, 8%) and the trisbrominated carboline(36 mg, 19%).

¹H NMR (d₆-DMSO, 500 MHz) δ 8.72 (s, 1H), 8.58 (d, 1H, J=1.5 Hz), 8.48(s, 1H), 7.70 (dd, 1H, J=1.5, 9.0 Hz), 7.58 (d, 1H, J=9.0 Hz).

ESI m/z 326.9 ([M+H]⁺, C₁₁H₇Br₂N₂ requires 326.9).

Step 2. Synthesis of3,6-Dibromo-9-(oxiran-2-ylmethyl)-9H-pyrido[3,4-b]indole

Following Representative Procedure 1,3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-pyrido[3,4-b]indole was preparedfrom 3,6-dibromo-∂-carboline in 73% yield.

¹H NMR (CDCl₃, 400 MHz) δ 8.62 (d, 1H, J=0.8 Hz), 8.17 (d, 1H, J=2.0Hz), 8.02 (d, 1H, J=1.2 Hz), 7.69 (dd, 1H, J=2.0, 8.8 Hz), 7.41 (d, 1H,J=8.8 Hz), 5.34 (br s, 1H), 4.73 (dd, 1H, J=2.4, 16.0 Hz), 4.27 (dd, 1H,J=5.2, 16.0 Hz), 3.32 (m, 1H), 2.83 (dd, 1H, J=4.0, 4.4 Hz), 2.49 (dd,1H, J=2.4, 4.4 Hz).

ESI m/z 382.9 ([M+H]⁺, C₁₄H₁₁Br₂N₂O requires 382.9).

Step 3. Synthesis of1-(3,6-Dibromo-9H-pyrido[3,4-b]indol-9-yl)-3-(phenylamino)propan-2-ol

Following Representative Procedure2,1-(3,6-dibromo-9H-pyrido[3,4-b]indol-9-yl)-3-(phenylamino)propan-2-olwas prepared from3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-pyrido[3,4-b]indole in 14% yieldafter purification by preparative TLC.

¹H NMR (CDCl₃, 500 MHz) δ 8.64 (s, 1H), 8.18 (d, 1H, J=2.0 Hz), 7.99 (s,1H), 7.66 (dd, 1H, J=1.5, 9.0 Hz), 7.40 (d, 1H, J=9.0 Hz), 7.18 (dd, 2H,J=7.5 Hz), 6.76 (t, 1H, J=7.5 Hz), 6.63 (d, 2H, J=8.5 Hz), 5.33 (br s,1H), 4.38-4.49 (m, 3H), 3.37 (dd, 1H, J=4.0, 13.0 Hz), 3.21 (dd, 1H,J=7.0, 13.0 Hz)

¹³C NMR (CDCl₃, 125 MHz) δ 147.7, 141.2, 137.0, 132.6, 132.5, 130.9,130.1, 129.7 (2C), 125.0, 122.0, 119.0, 118.6, 113.8 (2C), 113.4, 111.9,69.6, 48.1, 47.9

ESI m/z 475.9 ([M+H]⁺, C₂₀H₁₈Br₂N₃O requires 476.0)

Example 141-(3-Azidophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol

Following Representative Procedure 2, Example 14 was prepared in 14%yield.

¹H NMR (CDCl₃, 500 MHz) δ 8.13 (d, 2H, J=2.0 Hz), 7.53 (dd, 2H, J=2.0,8.5 Hz), 7.31 (d, 2H, J=8.5 Hz), 7.12 (t, 1H, J=8.0 Hz), 6.44 (dd, 1H,J=1.5, 8.0 Hz), 6.36 (dd, 1H, J=1.5, 8.0 Hz), 6.20 (dd, 1H, J=2.0 Hz),4.35-4.41 (m, 3H), 4.10 (br s, 1H), 3.31 (dd, 1H, J=3.0, 13.0 Hz), 3.17(dd, 1H, J=6.5, 13.0 Hz), 2.11 (br s, 1H)

ESI m/z 513.9 ([M+H]⁺, C₂₁H₁₈Br₂N₅O requires 514.0)

Example 15 1,3-Bis(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol

3,6-Dibromocarbazole (0.050 g, 0.154 mmol) was dissolved in DMF (1.5 mL)and cooled to 0° C. NaH (60% dispersion in mineral oil, 0.007 g, 0.169mmol) was added and the reaction was stirred for 45 min at 0° C.3,6-Dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (0.059 g, 0.154 mmol) wasadded and the reaction was stirred at ambient temperature for 24 h. Uponconsumption of the starting material by TLC, the reaction waspartitioned between EtOAc and H₂O. The aqueous layer was washed 3× withEtOAc, and the combined organics were washed with saturated aqueousNaCl, dried over Na₂SO₄, filtered, and concentrated in vacuo. The cruderesidue was purified by chromatography (SiO₂, 0-50% EtOAc/Hexane) toafford the desired product (37 mg, 34%).

¹H NMR (acetone-d₆, 400 MHz) δ 8.36 (d, 4H, J=2.0 Hz), 7.64 (d, 4H,J=8.8 Hz), 7.56 (dd, 4H, J=2.0, 8.8 Hz), 4.72 (m, 5H), 2.78 (br s, 1H)

¹³C NMR (acetone-d₆, 100 MHz) δ 141.2 (4C), 129.8 (4C), 124.6 (4C),124.1 (4C), 112.9 (4C), 112.7 (4C), 70.3, 48.3 (2C).

ESI m/z 747.0 ([M+CO₂H]⁻, C₂₈H₁₉Br₄N₂O₃ requires 746.8)

Example 161-(9H-Carbazol-9-yl)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol

Following a procedure analogous to that used to prepare Example 15,Example 16 was prepared in 48% yield.

¹H NMR (acetone-d₆, 400 MHz) δ 8.36 (m, 2H), 8.14 (d, 2H, J=8.0 Hz),7.63 (d, 2H, J=8.4 Hz), 7.55 (s, 2H), 7.42 (dt, 2H, J=1.2, 7.2 Hz), 7.20(dt, 2H, J=0.8, 7.2 Hz), 4.76 (m, 1H), 4.64-4.72 (m, 4H), 2.77 (br s,1H).

¹³C NMR (acetone-d₆, 100 MHz) δ 142.0 (2C), 141.0 (2C), 129.8 (2C),126.6 (2C), 124.5 (2C), 124.1 (2C), 123.8 (2C), 121.0 (2C), 119.9 (2C),112.7 (2C), 112.6 (2C), 110.5 (2C), 70.3, 48.4, 48.1.

ESI m/z 591.0 ([M+CO₂H]⁻, C₂₈H₂₁Br₂N₂O₃ requires 591.0).

Example 173-(3,6-Dibromo-9H-carbazol-9-yl)-2-hydroxy-N-(3-methoxyphenyl)-propanamide

Step 1. Synthesis of Methyl3-(3,6-Dibromo-9H-carbazol-9-yl)-2-hydroxypropanoate

3,6-Dibromocarbazole (0.300 g, 0.923 mmol) was dissolved in DMF (1.2 mL)and cooled to 0° C. NaH (60% dispersion in mineral oil, 0.074 g, 1.846mmol) was added and the reaction stirred for 1 h at 0° C. Methylglycidate (0.471 g, 4.615 mmol) was added and the reaction was stirredand warmed to ambient temperature over 3.5 h. Upon completion by TLC thereaction mixture was partitioned between EtOAc and H₂O. The aqueouslayer was extracted 3× with EtOAc, and the combined organics were washedwith saturated aqueous NaCl, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude residue was purified by chromatography(SiO₂, 0-30% EtOAc/Hexane) to afford the desired product (125 mg, 32%).

¹H NMR (CDCl₃, 500 MHz) δ 8.10 (d, 2H, J=2.0 Hz), 7.53 (dd, 2H, J=2.0,9.0 Hz), 7.36 (d, 2H, J=9.0 Hz), 4.63-4.55 (m, 3H), 3.69 (s, 3H), 2.94(d, 1H, J=5.5 Hz).

ESI m/z 425.8 ([M+H]⁺, C₁₆H₁₄Br₂NO₃ requires 425.9)

Step 2. Synthesis of 3-(3,6-Dibromo-9H-carbazol-9-yl)-2-hydroxypropanoicacid

NaOH (0.64 mL, 1M solution in H₂O) was added to a suspension of methyl3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropanoate (0.055 g, 0.129mmol) in EtOH (2.6 mL) and the reaction was stirred at ambienttemperature for 2.5 h. The reaction was concentrated in vacuo and theresidue was acidified with 1N aqueous HCl. The mixture was extractedwith EtOAc (3×), and the combined organics were washed with saturatedaqueous NaCl, dried over Na₂SO₄, filtered, and concentrated in vacuo toafford the desired product as a white solid (53 mg, 99%).

¹H NMR (CDCl₃, 500 MHz) δ 8.10 (d, 2H, J=1.5 Hz), 7.52 (dd, 2H, J=1.5,8.5 Hz), 7.40 (d, 2H, J=9.0 Hz), 4.68 (m, 2H), 4.60 (dd, 1H, J=6.5, 15.5Hz).

ESI m/z 411.9 ([M+H]⁺, C₁₅H₁₂Br₂NO₃ requires 411.9)

Step 3. Synthesis of3-(3,6-Dibromo-9H-carbazol-9-yl)-2-hydroxy-N-(3-methoxyphenyl)-propanamide

3-(3,6-Dibromo-9H-carbazol-9-yl)-2-hydroxypropanoic acid (0.025 g, 0.061mmol) was suspended in anhydrous CH₂Cl₂ and cooled to 0° C. Thionylchloride (0.005 mL, 0.073 mmol) was added dropwise and the reaction wasstirred at 0° C. for 1 h. m-Anisidine (0.008 mL, 0.073 mmol) and Et₃N(0.010 mL, 0.073 mmol) were added and the reaction was allowed to warmto ambient temperature over 2.5 h. Upon completion, the solution waspartitioned between EtOAc and H₂O. The aqueous layer was washed 3× withEtOAc, and the combined organics were washed with saturated aqueousNaCl, dried over Na₂SO₄, filtered, and concentrated in vacuo. The cruderesidue was purified by chromatography (SiO₂, 0-30% EtOAc/Hexane) toafford the desired product (15 mg, 48%).

¹H NMR (acetone-d₆, 500 MHz) δ 9.22 (br s, 1H), 8.34 (d, 2H, J=1.5 Hz),7.65 (d, 2H, J=8.5 Hz), 7.59 (dd, 2H, J=4.0, 8.5 Hz), 7.42 (dd, 1H,J=2.0 Hz), 7.24 (m, 1H), 7.20 (dd, 1H, J=8.0 Hz), 6.67 (dd, 1H, J=2.0,8.0 Hz), 5.56 (br s, 1H), 4.82 (m, 1H), 4.73 (m, 2H), 3.77 (s, 3H)

¹³C NMR (CDCl₃, 100 MHz) δ 170.9, 161.1, 141.1, 140.3, 130.3 (2C), 129.8(2C), 124.6 (2C), 124.0 (2C), 113.1 (2C), 112.8 (2C), 112.7, 110.5,106.4, 72.7, 55.6, 48.4.

ESI m/z 514.9 ([M−H]⁻, C₂₂H₁₇Br₂N₂O₃ requires 515.0)

Example 18 Ethyl5-(2-Hydroxy-3-(3-methoxyphenylamino)propyl)-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Step 1. Synthesis of Ethyl8-Methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Following a literature procedure (Harbert, C. A.; Plattner, J. J.;Welch, W. M.; Weissman, A.; Koe, B. K. J. Med. Chem. 1980, 23, 635-643)p-tolylhydrazine hydrochloride (0.500 g, 3.15 mmol) and1-carbethoxy-4-piperidone (0.18 mL, 1.17 mmol) were suspended in EtOH(0.880 mL) and heated to reflux for 2 hours. The reaction mixture wasremoved from heat and allowed to stand overnight at ambient temperature.The resulting mixture was filtered and washed with 50% aqueous EtOH toafford the desired product as a beige powder (259 mg, 86%).

¹H NMR (CDCl₃, 500 MHz) δ 7.73 (br s, 1H), 7.23 (s, 1H), 7.18 (d, 1H,J=8.0 Hz), 6.96 (d, 1H, J=8.0 Hz), 4.64 (br s, 2H), 4.18 (q, 2H, J=7.0Hz), 3.85 (m, 2H), 2.81 (br s, 2H), 2.42 (s, 3H), 1.28 (t, 3H, J=7.0Hz).

Step 2. Synthesis of Ethyl8-Methyl-5-(oxiran-2-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Ethyl 8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(0.025 g, 0.097 mmol) was dissolved in anhydrous degassed THF and wascooled to −78° C. A solution of n-BuLi (0.082 mL, 1.78 M in hexanes) wasadded dropwise and the reaction was stirred at −78° C. for 30 min.Epibromohydrin (0.016 mL, 0.194 mmol) was added and the reaction wasallowed to warm slowly to ambient temperature. After 3.5 h,epibromohydrin (0.008 mL, 0.097 mmol) was added and the reaction wasstirred overnight at ambient temperature. Upon completion, saturatedaqueous NH4Cl was added to quench the reaction and the mixture wasextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The crude residuewas purified by chromatography (SiO₂, 0-50% EtOAc/Hexane) to afford thedesired product (15 mg, 49%).

¹H NMR (CDCl₃, 500 MHz) δ 7.19 (m, 1H), 7.00 (d, 1H, J=8.5 Hz), 4.65 (brs, 2H), 4.32 (dd, 1H, J=3.0, 15.5 Hz), 4.18 (q, 2H, J=7.0 Hz), 4.08 (dd,1H, J=5.0, 15.5 Hz), 3.85 (m, 2H), 3.18 (m, 1H), 2.81 (br s, 2H), 2.73(dd, 1H, J=4.0, 4.5 Hz), 2.44 (s, 3H), 2.38 (br s, 1H), 1.29 (t, 3H,J=7.0 Hz)

Step 3. Synthesis of Ethyl5-(2-Hydroxy-3-(3-methoxyphenylamino)propyl)-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Following a literature procedure (Chakraborti, A. K.; Rudrawar, S.;Kondaskar, A. Eur. J. Org. Chem. 2004, 3597-3600) LiBr (0.001 g, 0.010mmol) and m-anisidine (0.011 mL, 0.102 mmol) were added to ethyl8-Methyl-5-(oxiran-2-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(0.032 g, 0.102 mmol) and stirred vigorously at ambient temperatureovernight. Upon completion the reaction was partitioned betweenEtOAc/H₂O, and the organic layer was concentrated to an orange oil. Thecrude residue was purified by chromatography (SiO₂, 0-50% EtOAc/Hexane)to afford the desired product (30 mg, 67%).

¹H NMR (CDCl₃, 500 MHz) δ 7.23 (br s, 1H), 7.17 (d, 1H, J=8.0 Hz), 7.05(dd, 1H, J=8.0 Hz), 6.97 (d, 1H, J=8.5 Hz), 6.28 (dd, 1H, J=1.5, 8.0Hz), 6.19 (d, 1H, J=8.0 Hz), 6.11 (br s, 1H), 4.64 (br s, 2H), 4.18 (m,1H), 4.16 (q, 2H, J=7.5 Hz), 4.12 (m, 1H), 3.80 (br s, 2H), 3.71 (s,3H), 3.23 (dd, 1H, J=3.5, 13.0 Hz), 3.07 (dd, 1H, J=7.5, 13.0 Hz), 2.83(m, 1H), 2.76 (m, 1H), 2.42 (s, 3H), 1.27 (t, 3H, J=7.0 Hz).

ESI m/z 438.2 ([M+H]⁺, C₂₅H₃₂N₃O₄ requires 438.2).

Example 19 4-(3,6-dibromo-9H-carbazol-9-yl)-1-(phenylamino)butan-2-ol

Step 1. Synthesis of 3,6-dibromo-9-(2-(oxiran-2-yl)ethyl)-9H-carbazole

Crushed KOH (0.0054 g, 0.0954 mmol, 1.2 equiv) was added to3,6-dibromocarbazole (0.0258 g, 0.0795 mmol, 1 equiv.) in 0.5 mL DMFsolution and the mixture was stirred for 30 min. 1-Bromo-3,4-epoxybutane(0.0300 g, 0.199 mmol) in 0.5 mL DMF solution was dropwise added intothe mixture and it was stirred at room temperature for overnight.Reaction crude was diluted with 20 mL EtOAc and washed with water 5×10mL. The organic layer was dried over anhydrous Na₂SO₄ and evaporated toafford 31.2 mg white solid as product, yield 97.9%.

¹H NMR (CDCl₃, 400 MHz) δ ppm 1.65-1.81 (m, 1H) 2.13-2.27 (m, 1H) 2.34(dd, J=4.88, 2.64 Hz, 1H) 2.64 (dd, J=4.78, 4.05 Hz, 1H) 2.69-2.80 (m,1H) 4.26-4.54 (m, 2H) 7.27 (d, J=8.69 Hz, 2H) 7.50 (dd, J=8.69, 1.90 Hz,2H) 8.08 (d, J=1.90 Hz, 2H)

Step 2. Synthesis of4-(3,6-dibromo-9H-carbazol-9-yl)-1-(phenylamino)butan-2-ol

According to Representative Procedure 2, Example 19 was isolated as awhite solid in 31% yield.

¹H NMR (CDCl₃, 400 MHz) ppm 1.87-1.98 (m, 1H) 2.05-2.14 (m, 1H)2.99-3.07 (dd, J=13.24, 3.43 Hz, 1H) 3.09-3.17 (dd, J=13.24, 8.27 Hz,1H) 3.60-3.74 (m, 1H) 4.39-4.48 (m, 1H) 4.51-4.60 (m, 1H) 6.57 (d,J=7.71 Hz, 2H) 6.74 (t, J=7.34 Hz, 1H) 7.15 (dd, J=8.27, 7.59 Hz, 2H)7.38 (d, J=8.69 Hz, 2H) 7.56 (dd, J=8.69, 1.90 Hz, 2H) 8.14 (d, J=1.85Hz, 2H)

¹³C NMR (CDCl₃, 500 MHz) δ=148.1, 139.6, 129.6, 129.4, 123.8, 123.6,118.7, 113.6, 112.4, 110.8, 67.7, 51.0, 39.9, 33.7.

m/z (ESI): 486.9 (M+H⁺) ([M+1] for C22H20Br2N2O requires 467.0)

Example 20 N-(3-(3,6-dibromo-9H-carbazol-9-yl)propyl)aniline

Step 1. Synthesis of 3,6-dibromo-9-(3-bromopropyl)-9H-carbazole

Crushed KOH (0.0673 g, 1.20 mmol, 1.2 equiv) was added to3,6-dibromocarbazole (0.3250 g, 1.00 mmol) in 2 mL DMF solution and themixture was stirred for 30 min. 1,3-dibromopropane (0.5047 g, 2.50 mmol,2.5 equiv) in 3 mL DMF solution was added dropwise into the mixture andit was stirred at room temperature overnight. The crude reaction mixturewas diluted with 30 mL EtOAc and washed with 1M HCl 2×10 mL and water3×10 mL. The organic layer was dried over anhydrous Na₂SO₄ andevaporated to afford the crude product, which was subjected to silicagel chromatography using Hexanes/EtOAc to afford 0.1275 g colorless oilas product, yield 28.6%.

¹H NMR (CDCl₃, 400 MHz) δ ppm 2.24-2.44 (m, 2H) 3.29 (t, J=6.05 Hz, 2H)4.33 (t, J=6.59 Hz, 2H) 7.26 (d, J=8.83 Hz, 2H) 7.51 (dd, J=8.69, 1.95Hz, 2H) 8.02 (d, J=1.71 Hz, 2H)

Step 2. Synthesis ofN-(3-(3,6-dibromo-9H-carbazol-9-yl)propyl)-2-nitro-N-phenylbenzenesulfonamide

Crushed KOH (0.0024 g, 0.0431 mmol) was added to2-nitro-N-phenylbenzenesulfonamide (0.0100 g, 0.0359 mmol) in 0.2 mL DMFsolution and the mixture was stirred for 30 min.3,6-dibromo-9-(3-bromopropyl)-9H-carbazole (Example 35, 0.0240 g, 0.0538mmol) in 0.3 mL DMF solution was added dropwise into the mixture and itwas stirred at room temperature overnight. The crude reaction mixturewas diluted with 20 mL EtOAc and washed with water 5×10 mL. The organiclayer was dried over anhydrous Na₂SO₄ and evaporated to afford the crudeproduct, which was subjected to silica gel chromatography usingHexanes/EtOAc to afford 0.0082 g white solid as impure product, purity66.9% (impurity is starting Ns-aniline; used without additionalpurification), yield 35.5%.

¹H NMR (CDCl₃, 400 MHz) δ ppm 1.89-2.01 (m, 2H) 3.95 (t, J=6.61 Hz, 2H)4.32-4.38 (m, 2H) 7.15 (s, 1H) 7.17 (s, 1H) 7.18-7.25 (m, 3H) 7.32 (d,J=3.66 Hz, 2H) 7.41-7.44 (m, 2H) 7.51 (dd, J=8.69, 1.95 Hz, 2H)7.59-7.71 (m, 2H) 8.09 (d, J=1.90 Hz, 2H)

Step 3. Synthesis of N-(3-(3,6-dibromo-9H-carbazol-9-yl)propyl)aniline

N-(3-(3,6-dibromo-9H-carbazol-9-yl)propyl)-2-nitro-N-phenylbenzenesulfonamide(0.0378 g, 0.0588 mmol, 1 equiv), cesium carbonate (0.0574 g, 0.176mmol, 3 equiv) and benzenethiol (0.0194 g, 0.176 mmol) were mixed in 1mL anhydrous THF. The mixture was stirred at room temperature for 3hours. THF was removed under vacuum and the residue was purified bysilica gel chromatography using Hexanes/EtOAc to afford 0.0164 gcolorless oil as product, yield 60.9%.

¹H NMR (CDCl₃, 400 MHz) δ ppm 2.08-2.29 (m, 2H) 3.09 (t, J=6.56 Hz, 2H)3.55 (br. s., 1H) 4.37 (t, J=6.69 Hz, 2H) 6.53 (dd, J=8.56, 0.95 Hz, 2H)6.73 (t, J=7.32 Hz, 1H) 7.16 (dd, J=8.49, 7.37 Hz, 2H) 7.25 (d, J=8.69Hz, 2H) 7.51 (dd, J=8.69, 1.95 Hz, 2H) 8.12 (d, J=1.85 Hz, 2H)

¹³C NMR (CDCl₃, 400 MHz) δ=148.0, 139.5, 129.6, 129.4, 123.7, 123.6,118.2, 113.3, 112.4, 110.5, 41.4, 40.9, 28.9

MS (ESI), m/z: 456.9 [M+H]+([M+H]+ for C21H18Br2N2 requires 457.0)

Example 21 1-(3,6-dibromo-9H-carbazol-9-yl)-4-(phenylamino)butan-2-ol

Step 1. Synthesis of N-(but-3-enyl)-2-nitro-N-phenylbenzenesulfonamide

Crushed KOH (0.0484 g, 0.862 mmol, 1.2 equiv) was added to2-nitro-N-phenylbenzenesulfonamide (0.200 g, 0.719 mmol) in 1 mL DMF,and the mixture was stirred for 30 min. 4-Bromo-1-butene (0.2426 g, 1.80mmol) in 2 mL DMF solution was added dropwise into the mixture and itwas stirred at room temperature overnight. The reaction mixture wasdiluted with 30 mL EtOAc and washed with 1M HCl 2×10 mL and water 3×10mL. The organic layer was dried over anhydrous Na₂SO₄ and evaporated toafford the crude product, which was subjected to silica gelchromatography using Hexanes/EtOAc to afford 0.1546 g white solid, yield63.5%.

¹H NMR (CDCl₃, 400 MHz) δ ppm 2.20 (q, J=6.90 Hz, 2H) 3.83 (t, J=7.15Hz, 2H) 5.00 (d, J=4.39 Hz, 1H) 5.03 (s, 1H) 5.64-5.83 (m, 1H) 7.14-7.21(m, 3H) 7.30 (d, J=1.85 Hz, 2H) 7.42-7.46 (m, 2H) 7.52-7.58 (m, 1H)7.60-7.66 (m, 1H)

Step 2. Synthesis of2-nitro-N-(2-(oxiran-2-yl)ethyl)-N-phenylbenzenesulfonamide

mCPBA (77%, 0.0550 g, 0.246 mmol) was added toN-(but-3-enyl)-2-nitro-N-phenylbenzenesulfonamide (0.0653 g, 0.196 mmol)in 1 mL CHCl₃ at 0° C. The mixture was stirred at 0° C. for 30 min, thengradually warmed up to room temperature and continued to stir for 18 hr.After TLC showed the disappearance of starting material, the reactionmixture was diluted with a 1:1 mixture of water and saturated NaHCO₃(2×10 mL) and water (10 mL). The organic layer was dried over anhydrousNa₂SO₄ and evaporated to afford the crude product, which was subjectedto silica gel chromatography using Hexanes/EtOAc to afford 0.0662 gcolorless oil as product, yield 96.9%.

¹H NMR (CDCl₃, 400 MHz) ppm 1.66-1.79 (m, 2H) 2.46 (dd, J=4.95, 2.66 Hz,1H) 2.70-2.80 (m, 1H) 2.93-3.03 (m, 1H) 3.87-4.07 (m, 2H) 7.19-7.23 (m,2H) 7.28-7.34 (m, 3H) 7.43-7.47 (m, 2H) 7.57-7.66 (m, 2H).

MS (ESI) m/z: 371.0 (M+Na⁺) ([M+Na]+ for C₁₆H₁₆N₂O₅S requires 371.1)

Step 3. Synthesis of N-(2-(oxiran-2-yl)ethyl)aniline

Prepared from2-nitro-N-(2-(oxiran-2-yl)ethyl)-N-phenylbenzenesulfonamide using ananalogous procedure as used to prepare the compound of Example 20.

¹H NMR (CDCl₃, 400 MHz) δ ppm 1.64-1.79 (m, 1H) 1.98-2.15 (m, 1H) 2.55(dd, J=4.90, 2.71 Hz, 1H) 2.79 (t, J=4.44 Hz, 1H) 3.00-3.10 (m, 1H) 3.31(t, J=6.64 Hz, 2H) 3.87 (br. s., 1H) 6.62 (d, J=7.71 Hz, 2H) 6.71 (t,J=7.32 Hz, 1H) 7.18 (dd, J=8.49, 7.37 Hz, 2H)

MS (ESI) m/z: 164.1 (M+H⁺) ([M+1]+ for C₁₀H₁₃NO requires 164.1)

Step 4. Synthesis of1-(3,6-dibromo-9H-carbazol-9-yl)-4-(phenylamino)butan-2-ol

NaH (60% dispersed in mineral oil, 0.0018 g, 0.0452 mmol) was added to asolution of 3,6-dibromocarbazole (0.0147 g, 0.0452 mmol) in 0.5 mLanhydrous THF and the mixture was stirred for 15 min.N-(2-(oxiran-2-yl)ethyl)aniline (0.0067 g, 0.0410 mmol) in 1.5 mLanhydrous THF solution was added dropwise and the resulting mixture wasstirred at 60° C. overnight. THF was removed under vacuum and theresidue was dissolved in 10 mL EtOAc and washed with water 2×5 mL. Theorganic layer was dried over anhydrous Na₂SO₄ and evaporated to affordthe crude product, which was subjected to silica gel chromatographyusing Hexanes/EtOAc to afford 0.0115 g colorless oil; yield 57.5%.

¹H NMR (CDCl₃, 400 MHz) δ ppm 1.76-1.95 (m, 2H) 3.22-3.41 (m, 2H)4.20-4.38 (m, 3H) 6.63 (d, J=8.49 Hz, 2H) 6.76 (t, J=7.32 Hz, 1H) 7.18(t, J=7.95 Hz, 2H) 7.31 (d, J=8.74 Hz, 2H) 7.54 (dd, J=8.69, 1.95 Hz,2H) 8.12 (d, J=1.95 Hz, 2H)

¹³C NMR (CDCl₃, 400 MHz) δ=148.1, 139.9, 129.6, 129.5, 123.8, 123.5,118.7, 113.9, 112.7, 111.1, 70.7, 50.0, 42.2, 34.1.

MS (ESI) m/z: 531.0 [M+HCOO]^(˜)486.9 [M+H]⁺([M+H]+ for C₂₂H₂₀Br₂N₂Orequires 487.0)

Example 221-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-2-ylamino)propan-2-ol

Step 1. Synthesis of 1-amino-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol

A solution of NH₃ (9.4 mL of 7M in MeOH, 65.6 mmol) was added to3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (0.500 g, 1.31 mmol). Thevial was tightly sealed and the reaction mixture was heated to 100° C.and stirred for 1 hour. Volatile components were removed under vacuum.The residue was suspended in CH₂Cl₂ and the white precipitate wasfiltered. The filtrate was saved and CH₂Cl₂ was removed under vacuum toafford 0.3413 g white solid as crude product, which contained about 50%unidentified side-product. This crude product was used as is in nextstep without any further purification. Purification by flashchromatography on silica gel provided pure material.

¹H NMR (CDCl₃, 400 MHz) δ ppm 2.61 (dd, J=12.66, 7.78 Hz, 1H) 2.90 (dd,J=12.52, 4.03 Hz, 1H) 3.96-4.06 (m, 1H) 4.32 (d, J=5.81 Hz, 2H) 7.36 (d,J=8.74 Hz, 2H) 7.55 (dd, J=8.69, 1.95 Hz, 2H) 8.13 (d, J=1.90 Hz, 2H)

MS (ESI) m/z: 396.9 (M+H⁺) ([M+H]+ for C15H14Br2N20 requires 397.0)

Step 2. Synthesis of5-((3,6-dibromo-9H-carbazol-9-yl)methyl)oxazolidin-2-one

A solution of triphosgene (0.0890 g, 0.300 mmol, 0.35 equiv) in 2 mLanhydrous CH₂Cl₂ was added dropwise to a solution of1-amino-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol (0.3413 g, 0.857mmol) and Et₃N (0.1909 g, 1.886 mmol) in 1 mL CH₂Cl₂ under N₂ atmosphereat 4° C. The reaction mixture was stirred for 15 min at 4° C. and thenwarmed to room temperature and stirred for 1 hour. CH₂Cl₂ was removedunder vacuum. Saturated NH₄Cl (5 mL) and 10 mL EtOAc was added to theresidue and stirred for 20 min. Then the aqueous layer was separated andthe organic layer was washed with water 2×10 mL. The combined aqueouslayers were extracted with EtOAc, dried over anhydrous Na₂SO₄ andevaporated to afford the crude product, which was subjected to silicagel chromatography using CH₂Cl₂/EtOAc to afford 0.1173 g white solid,yield 20.0% over 2 steps.

¹H NMR (CDCl₃, 400 MHz) δ ppm 3.37 (dd, J=8.98, 6.34 Hz, 1H) 3.67 (t,J=8.49 Hz, 1H) 4.54 (dd, J=5.22, 1.81 Hz, 2H) 5.02 (br. s., 1H)5.05-5.14 (m, 1H) 7.31 (d, J=8.69 Hz, 2H) 7.58 (dd, J=8.69, 1.85 Hz, 2H)8.14 (d, J=1.85 Hz, 2H)

MS (ESI) m/z: 466.9 [M+HCOO]⁻ ([M+HCOO]— for C₁₆H₁₂Br₂N₂O₂ requires466.9.

Step 3. Synthesis of5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(pyridin-2-yl)oxazolidin-2-one

A mixture of 5-((3,6-dibromo-9H-carbazol-9-yl)methyl)oxazolidin-2-one(0.0195 g, 0.0460 mmol), 2-iodopyridine (0.0209 g, 0.102 mmol), CuI(0.0009 g, 0.00460 mmol), and K₂CO₃ (0.0058 g, 0.0418 mmol) in 0.5 mL ofDMSO was sealed tightly in a vial and heated at 130° C. for 12 hours.The reaction mixture was cooled and diluted with 20 mL EtOAc and washedwith water 5×10 mL. The organic layer was dried over anhydrous Na₂SO₄and evaporated to afford the crude product, which was subjected tosilica gel chromatography using CH₂Cl₂/EtOAc as elute to afford 0.0183 gwhite solid as product, yield 79.4%.

¹H NMR (CDCl₃, 400 MHz) δ ppm 4.04 (dd, J=10.79, 7.08 Hz, 1H) 4.36 (dd,J=10.69, 8.74 Hz, 1H) 4.60 (d, J=5.03 Hz, 2H) 5.02-5.16 (m, 1H) 7.02 (t,J=6.08 Hz, 1H) 7.35 (d, J=8.69 Hz, 2H) 7.59 (dd, J=8.66, 1.73 Hz, 2H)7.68 (t, J=7.88 Hz, 1H) 8.11 (s, 1H) 8.13 (d, J=1.32 Hz, 2H) 8.25 (d,J=4.93 Hz, 1H)

MS (ESI) m/z: 543.9 [M+HCOO]⁻ ([M+HCOO]— for C₂₁H₁₅Br₂N₃O₂ requires544.0)

Step 4. Synthesis of1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-2-ylamino)propan-2-ol

LiOH.H₂O (0.0076 g, 0.182 mmol, 10 equiv) was added to5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(pyridin-2-yl)oxazolidin-2-one(0.0091 g, 0.0182 mmol) in a mixture of 208 μL THF and 23 μL H₂O(v/v=9:1). The mixture was stirred at room temperature for 7 days. Thereaction mixture was purified by silica gel chromatography usingCH₂Cl₂/EtOAc as elute to afford 0.0071 g white solid as product, yield41.0%.

¹H NMR (CDCl₃, 400 MHz) δ ppm 2.27-2.44 (m, 1H) 3.15-3.32 (m, 1H) 3.44(dd, J=15.23, 5.03 Hz, 1H) 4.26-4.41 (m, 3H) 4.52 (t, J=5.00 Hz, 1H)6.46 (d, J=8.00 Hz, 1H) 6.66 (t, J=6.20 Hz, 1H) 7.37 (d, J=8.74 Hz, 2H)7.40-7.48 (m, 1H) 7.56 (dd, J=8.69, 1.90 Hz, 2H) 8.04 (d, J=4.49 Hz, 1H)8.14 (d, J=1.85 Hz, 2H)

¹³C NMR (CDCl₃, 400 MHz) δ=158.6, 146.7, 139.5, 138.1, 129.2, 123.6,123.3, 113.9, 112.3, 110.9, 109.6, 70.5, 47.4, 46.8

MS (ESI) m/z: 518.0 [M+HCOO]⁻ ([M+HCOO]— for C₂₀H₁₇Br₂N₃O requires518.0.

Example 231-(3,6-dibromo-9H-carbazol-9-yl)-3-((3-methoxyphenyl)(methyl)-amino)propan-2-ol

Synthesized using a similar synthetic procedure analogous toRepresentative Procedure 2.

Example 253-amino-1-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)pyridinium

Example 25 was synthesized using a similar synthetic procedure analogousto Representative Procedure 2.

Example 261-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyrimidin-2-ylamino)propan-2-ol

To a 4 ml vial was added the corresponding primary amine (34.8 mg, 0.087mmol), 2-chloropyrimidine (10.3 mg, 0.090 mmol) and dimethylformamide(1.5 ml, 0.058 M). The reaction was heated at 100° C. overnight. Thecooled reaction mixture was diluted with EtOAc and washed several timeswith water and brine. The organic layer was dried over Na₂SO₄, filteredand condensed. The crude mixture was subjected to chromatography onsilica gel (20% MeOH/CH₂Cl₂).

¹H NMR (CDCl₃, 400 MHz) δ 8.26 (d, 2H, J=4.94 Hz), 8.14 (d, 2H, J=1.88Hz), 7.56 (dd, 2H, J=6.7, 1.9 Hz), 7.37 (d, 2H, J=8.7 Hz), 6.63 (t, 1H,J=4.9 Hz), 5.43 (t, 1H, J=5.71 Hz), 4.36 (s, 3H), 3.56 (m, 1H),3.30-3.38 (m, 1H).

¹³C NMR (CDCl₃, 126 MHz) §139.4, 29.5 (2C), 129.3 (2C), 123.7 (2C),123.4 (2C), 118.6 (2) (2C), 113.5 (2C), 112.3, 110.7 (2C), 67.6, 50.9,33.6.

MS (ESI) m/z: 474.9 [(M+1)⁺; C19H16Br2N40 (M) requires 474)].

The title compound of Example 26 can also be synthesized using aprocedure analogous to that described in Representative Procedure 2.

Example 28 1-(3,6-dibromo-9H-carbazol-9-yl)-3-methoxypropan-2-ol

Following Representative Procedure 1, Example 28 was prepared fromdibromocarbazole and methoxymethyloxirane

Example 29 1-(3,6-dibromo-9H-carbazol-9-yl)-4-phenylbutan-2-ol

Following Representative Procedure 1, Example 29 was prepared fromdibromocarbazole and 2-phenethyloxirane.

Example 30 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(1H-indol-1-yl)propan-2-ol

Following Representative Procedure 1, Example 30 was prepared fromdibromocarbazole and 1-(oxiran-2-ylmethyl)-1H-indole.

Example 313-(1-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)propan-1-ol

Example 31 was synthesized using a similar synthetic procedure analogousto Representative Procedure 2.

Example 321-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-ethoxyphenylamino)propan-2-ol

Example 32 was synthesized using a similar synthetic procedure analogousto Representative Procedure 2.

Example 331-(3,6-dibromo-9H-carbazol-9-yl)-3-(3,5-dimethyl-1H-pyrazol-1-yl)propan-2-ol

Example 33 was synthesized using a similar synthetic procedure analogousto Representative Procedure 2.

Example 361-(3-bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol

Step 1. 3-bromo-9-(oxiran-2-ylmethyl)-9H-carbazole

The title compound of Example 36, step 1 was prepared using a procedureanalogous to that described in representative procedure 1.

¹H NMR (CDCl₃, 400 MHz) δ=2.52 (dd, J=4.6, 2.6 Hz, 1H) 2.80 (t, J=4.3Hz, 1H) 3.33 (td, J=5.3, 2.2 Hz, 1H) 4.34 (dd, J=15.9, 4.9 Hz, 1H) 4.64(dd, J=15.9, 2.9 Hz, 1H) 7.26 (t, J=7.3 Hz, 1H) 7.35 (d, J=8.7 Hz, 1H)7.58-7.42 (m, 3H) 8.02 (d, J=5.1 Hz, 1H) 8.19 (d, J=1.7 Hz, 1H).

Step 2

The title compound was prepared from3-bromo-9-(oxiran-2-ylmethyl)-9H-carbazole using a procedure similar tothat described in representative procedure 2.

¹H NMR (CDCl₃, 400 MHz) δ=2.13 (d, J=3.0 Hz, 1H) 3.21 (dd, J=13.0, 6.5Hz, 1H) 3.35 (dd, J=13.0, 3.2 Hz, 1H) 3.72 (s, 3H) 4.03 (s, br, 1H)4.50-4.36 (m, 3H) 6.15 (t, J=2.3 Hz, 1H) 6.24 (dd, J=8.0, 2.2 Hz, 1H)6.32 (dd, J=8.2, 2.3 Hz, 1H) 7.08 (t, J=8.1 Hz, 1H) 7.30-7.24 (m, 1H)7.36 (d, J=8.7 Hz, 1H) 7.51-7.44 (m, 2H) 7.53 (dd, J=8.7, 1.9 Hz, 1H)8.05 (d, J=7.9 Hz, 1H) 8.21 (d, J=1.9 Hz, 1H)

¹³C NMR (CDCl₃, 400 MHz) 6=161.0, 149.4, 141.2, 139.6, 130.4, 128.8,126.9, 125.0, 123.3, 122.2, 120.8, 120.1, 112.4, 110.7, 109.4, 106.7,103.8, 99.7, 69.6, 55.3, 48.0, 47.4.

ESI m/z: 425.0 [(M+H⁺), C22H21BrN2O2 (M) requires 421.1].

Example 37N-(5-(3-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropylamino)phenoxy)pentyl)-2-(7-(dimethylamino)-2-oxo-2H-chromen-4-yl)acetamide

The coumarin was attached to Example 62 Compound using a known procedure(Alexander, M. D., Burkart, M. D., Leonard, M. S., Portonovo, P., Liang,B., Ding, X., Joullie, M. M., Gulledge, B. M., Aggen, J. B., Chamberlin,A. R., Sandler, J., Fenical, W., Cui, J., Gharpure, S. J., Polosukhin,A., Zhang, H-R., Evans, P. A., Richardson, A. D., Harper, M. K.,Ireland, C. M., Vong, B. G., Brady, T. P., Theodorakis, E. A., and LaClair, J. J. ChemBioChem, 2006, 7, 409-416.

Example 39N-(2-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropoxy)ethyl)-acetamide

Step 1.2-(2-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropoxy)ethyl)isoindoline-1,3-dione

Sodium hydride dispersion (31.6 mg, 0.79 mmol) was added to a solutionof N-(2-hydroxyethyl)-phthalimide (153.7 mg, 0.80 mmol) in anhydrous THF(1.2 ml, 0.67 M). The suspension is stirred for 15 minutes before theaddition of carbazole epoxide 2-A. The reaction was stirred at roomtemperature for five minutes and then at 60° C. for 1 hour. The cooledreaction was diluted with EtOAc and washed with water. The aqueous layerwas extracted and the combined organics were filtered over a celite pad.The Crude product was used without further purification. Yield=44%

¹H NMR (CDCl₃, 500 MHz) 8.12 (s, 2H), 7.85 (s, 2H), 7.72 (m, 2H), 7.55(d, 2H, J=8.5 Hz), 7.33 (d, 2H, J=8.7 Hz), 4.64 (d, 1H, J=16.1 Hz), 4.27(d, 1H), 3.88 (m, 4H), 3.31 (bs, 1H), 2.80 (m, 1H), 2.48 (m, 1H), 2.04(s, 1H).

MS (ESI), m/z: 614.9 [(M+HCOO)⁻; C25H20Br2N2O4 (M) requires 570].

Step 2. 1-(2-aminoethoxy)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol

Hydrazine hydrate (400 ul, 8.22 mmol) was added to a solution of thephthalimide prepared in step 1 above (53 mg, 0.093 mmol) in ethanol (2.0ml, 0.046 M). The reaction was stirred overnight, condensed and purifiedin 5-10% MeOH/DCM.

¹H NMR (CDCl₃, 500 MHz) 8.11 (s, 2H), 7.53 (dd, 2H, J=8.7, 1.8 Hz), 7.38(d, 2H, J=8.5 Hz), 4.37 (dm, 5H), 4.05 (t, 1H, J=6.8 Hz), 2.84 (m, 2H),2.62 (m, 1H)

MS (ESI), m/z: 440.9 [(M+1)⁺; C17H18Br2N2O2 (M) requires 440.0].

Step 3

The title compound of Example 39 was prepared as follows. Triethylamine(33.5 ul, 0.26 mmol) and acetic anhydride (17 ul, 0.18 mmol) were addedto a solution of amine XIII (71 mg, 0.16 mmol) in THF (3.0 ml, 0.053 M).The reaction was stirred overnight. The reaction mixture was dilutedwith EtOAc, washed with water, dried over Na₂SO₄, filtered andcondensed. The crude mixture was subjected to flash chromatography (5%MeOH/CH₂Cl₂).

¹H NMR (CDCl₃, 500 MHz) 8.13 (d, 2H, J=1.7 Hz, 7.55 (dd, 2H, J=8.7, 1.8Hz), 7.34 (d, 2H, 9.1 Hz), 5.78 (bs, 1H), 4.35 (ddd, 3H, J=6.2, 6.8 Hz),4.22 (m, 1H), 3.46 (m, 4H), 3.33 (dd, 1H, J=9.7, 5.4 Hz), 2.80 (bs, 1H),1.98 (s, 3H)

MS (ESI), m/z: 482.9 [(M+1)⁺; C₁₉H₂₀Br₂N203 (M) requires 482.0]

Example 401-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-3-ylamino)propan-2-ol

Step 1.5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(pyridin-3-yl)oxazolidin-2-one

A mixture of the corresponding N—H oxazolidinone (0.0390 g, 0.0920mmol), 3-iodopyridine (0.0419 g, 0.204 mmol), CuI (0.0018 g, 0.00920mmol), and K₂CO₃ (0.0116 g, 0.0837 mmol) in 0.5 mL of DMSO was heated at130° C. for 12 hours in a sealed vial. The reaction mixture was cooledand diluted with 20 mL EtOAc and washed with water 2×10 mL and brine2×10 mL. The organic layer was dried over anhydrous Na₂SO₄ andevaporated to afford the crude product (0.0383 g white solid, yield83.7%), which was used without further purification.

¹H NMR (CDCl₃, 400 MHz) δ=3.82 (dd, J=9.1, 6.6 Hz, 1H) 4.12 (dd, J=10.0,7.9 Hz, 1H) 4.72-4.55 (m, 2H) 5.15 (td, J=11.8, 5.4 Hz, 1H) 7.27 (dd,J=8.3, 4.9 Hz, 1H) 7.34 (d, J=8.7 Hz, 2H) 7.59 (dd, J=8.7, 1.9 Hz, 2H)8.03 (ddd, J=8.5, 2.6, 1.2 Hz, 1H) 8.14 (d, J=1.9 Hz, 2H) 8.37 (d, J=4.2Hz, 1H) 8.44 (s, 1H)

ESI m/z: 543.9 [(M+HCOO⁻); C21H15Br2N3O2 (M) requires 499].

Step 2

The title compound of Example 40 was prepared as follows. LiOH.H₂O(0.0097 g, 0.231 mmol) was added to5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(pyridin-3-yl)oxazolidin-2-one(0.0116 g, 0.0231 mmol) in a mixture of 265 μL, THF and 29 μL H₂O(v/v=9:1). The mixture was stirred at room temperature for 7 days. Thereaction mixture purified by silica gel chromatography using CHCl₃/MeOHas elute to afford 0.0087 g white solid as product, yield 79.3%.

¹H NMR (CDCl₃, 600 MHz) δ=3.15 (dd, J=12.6, 6.2 Hz, 1H) 3.30 (d, J=11.8Hz, 1H) 4.45-4.33 (m, 3H) 6.81 (d, J=7.4 Hz, 1H) 7.02 (s, br, 1H) 7.32(d, J=8.7 Hz, 2H) 7.52 (dd, J=8.7, 1.8 Hz, 2H) 7.83 (s, br, 2H) 8.11 (d,J=1.6 Hz, 2H)

¹³C NMR (CDCl₃, 400 MHz) 6=139.8, 139.5, 136.2, 130.0, 129.5, 124.1,123.8, 123.5, 119.7, 112.8, 110.9, 69.0, 47.6, 47.3

ESI m/z: 517.9 [(M+HCOO⁻); C20H17Br2N3O (M) requires 473].

Example 411-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-4-ylamino)propan-2-ol

Step 1.5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(pyridin-4-yl)oxazolidin-2-one

A mixture of the corresponding N—H oxazolidinone (0.0195 g, 0.0460mmol), 4-iodopyridine (0.0209 g, 0.102 mmol), CuI (0.0009 g, 0.00460mmol), and K₂CO₃ (0.0058 g, 0.0418 mmol) in 0.5 mL of DMSO was at 130°C. for 12 hours in a sealed vial. The reaction mixture was cooled anddiluted with 20 mL EtOAc and washed with brine (3×10 mL). The organiclayer was dried over anhydrous Na₂SO₄ and evaporated to afford the crudeproduct, which was further triturated from CH₂Cl₂ suspension by hexaneto afford 0.0187 g white solid as product, yield 74.6%.

¹H NMR (CDCl₃, 400 MHz) δ=3.77 (dd, J=9.4, 6.8 Hz, 1H) 4.08 (t, J=9.0Hz, 1H) 4.64 (d, J=4.6 Hz, 2H) 5.23-5.10 (m, 1H) 7.34 (d, J=8.7 Hz, 2H)7.37 (s, br, 2H) 7.61 (dd, J=8.6, 1.8 Hz, 2H) 8.16 (d, J=1.8 Hz, 2H)8.55 (s, br, 2H).

ESI m/z: 544.0 [(M+HCOO⁻); C21H15Br2N3O₂ (M) requires 499].

Step 2

The title compound of Example 41 was prepared as follows. LiOH.H₂O(0.0157 g, 0.373 mmol) was added to5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(pyridin-4-yl)oxazolidin-2-one(0.0187 g, 0.0373 mmol) in a mixture of 428 μL THF and 48 μL H₂O(v/v=9:1). The mixture was stirred at room temperature for 3 days. Thereaction mixture was diluted with 30 mL EtOAc and washed with brine 3×30mL. The organic layer was dried over anhydrous Na₂SO₄ and evaporated toafford the crude product, which did not require purification (0.0013 gwhite solid, 7.3%).

¹H NMR (d₆-Acetone, 400 MHz) δ=3.33 (dd, J=13.1, 6.4 Hz, 1H) 3.49 (dd,J=13.2, 4.4 Hz, 1H) 4.41 (td, J=7.6, 4.1 Hz, 1H) 4.51 (dd, J=15.0, 7.6Hz, 1H) 4.61 (dd, J=14.8, 3.4 Hz, 1H) 6.61 (s, 2H) 7.56 (d, J=8.6 Hz,2H) 7.62 (d, J=8.7 Hz, 2H) 8.10 (s, br, 2H) 8.37 (s, 2H)

¹³C NMR (d₆-Acetone, 400 MHz) δ=179.0, 149.6, 140.4, 129.0, 123.8,123.3, 112.1, 111.8, 107.8, 68.8, 47.6, 46.4

ESI m/z: 517.9 [(M+HCOO⁻); C20H17Br2N3O (M) requires 473].

Example 421-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(phenylamino)propan-2-ol

Example 42 was synthesized using a similar synthetic procedure analogousto Representative Procedure 2.

Example 43N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2,2-difluoropropyl)-3-methoxyaniline

Step 1.N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-oxopropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamide

The nosylate of the title compound of Example 62 (prepared according tothe procedures described herein) was oxidized with Dess-Martinperiodinane using a procedure similar to that described in Example 103.Quantitative yield.

¹H NMR (CDCl₃, 500 MHz) δ 8.24 (d, 2H, J=8.9 Hz), 8.14 (s, 2H), 7.68 (d,2H, J=9.1 Hz), 7.53 (d, 2H, J=8.6 Hz), 7.18 (t, 1H, J=8.7 Hz), 7.05 (t,2H, J=8.1 Hz), 6.87 (dd, 1H, J=8.3, 2.5 Hz) 5.21, (s, 2H), 4.30 (s, 2H),2.48 (s, 3H).

MS (ESI), m/z: 683.9 [(M−1)⁻; C28H21Br2N3O6S (M) require 685.0].

Step 2.N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2,2-difluoropropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamide

The title compound of Example 43, step 2 was prepared from the ketoneprepared in step 1 above using a procedure similar to that described inExample 103. Yield was quantitative and crude product was used withoutadditional purification.

¹H NMR (CDCl₃, 500 MHz) δ 8.31 (d, 2H, J=8.9 Hz), 8.11 (s, 2H), 7.77 (d,2H, J=8.9 Hz), 7.55 (dd, 2H, J=8.7, 1.8 Hz), 7.25 (m, 3H), 6.92 (dd, 1H,J=8.3, 2.0 Hz), 6.73 (m, 1H) 6.61, (d, 1H, J=7.7 Hz), 4.78 (t, 2H,T=14.7 Hz), 4.18 (t, 2H, J=11.2 Hz), 3.78 (s, 3H).

MS (ESI), m/z: 751.9 [(M+HCOO)⁻; C28H21Br2F2N3O5S (M) requires 707.0].

Step 3

The title compound of Example 43 was prepared as follows. The nosylgroup onN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2,2-difluoropropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamidewas removed using the procedure described in Representative Procedure 5.

¹H NMR (CDCl₃, 400 MHz) δ 8.11 (d, 2H, J=1.6 Hz), 7.49 (dd, 2H, J=8.7,2.0 Hz), 7.32 (d, 2H, J=8.9 Hz), 7.11 (t, 1H, J=8.2 Hz) 6.39 (dd, 1H,J=8.2, 2.3 Hz), 4.68 (t, 2H, J=13.2 Hz), 3.89 (t, 1H, J=7.0 Hz), 3.74(s, 3H), 3.47 (m, 2H)

MS (ESI), m/z: 566.9 [(M+HCOO)⁻; C₂₂H₁₈Br₂F2N2O (M) requires 522.0].

Example 45 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol

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Example 46 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(o-tolylamino)propan-2-ol

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Example 47 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(m-tolylamino)propan-2-ol

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Example 481-(3,6-dibromo-9H-carbazol-9-yl)-3-(2-methoxyphenylamino)propan-2-ol

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Example 501-(4-bromophenylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol

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Example 511-(4-bromophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol

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Example 521-(3,6-dibromo-9H-carbazol-9-yl)-3-(4-ethoxyphenylamino)propan-2-ol

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Example 531-(4-chlorophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol

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Example 541-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenethylamino)propan-2-ol

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Example 551-(3,6-dibromo-9H-carbazol-9-yl)-3-(2-hydroxyethylamino)propan-2-ol

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Example 561-(3,6-dibromo-9H-carbazol-9-yl)-3-(2,4-dimethoxyphenylamino)propan-2-ol

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Example 571-(3,6-dibromo-9H-carbazol-9-yl)-3-(2,3-dimethylphenylamino)propan-2-ol

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Example 581-(2-chlorophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol

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Example 591-(tert-butylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol

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Example 601-(3,6-dibromo-9H-carbazol-9-yl)-3-(isopropylamino)propan-2-ol

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Example 611-(3,6-dibromo-9H-carbazol-9-yl)-3-(4-methoxyphenylamino)propan-2-ol

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Example 621-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol

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Example 63 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(m-tolylamino)propan-2-ol

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Example 641-(3,6-dibromo-9H-carbazol-9-yl)-3-(3,5-dimethylphenylamino)propan-2-ol

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Example 651-(3,6-dibromo-9H-carbazol-9-yl)-3-(3,4-dimethylphenylamino)propan-2-ol

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Example 661-(3,6-dibromo-9H-carbazol-9-yl)-3-(3,4-dimethylphenylamino)propan-2-ol

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Example 671-(3,6-dibromo-9H-carbazol-9-yl)-3-(2,5-dimethylphenylamino)propan-2-ol

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Example 681-(4-bromophenylamino)-3-(2,3-dimethyl-1H-indol-1-yl)propan-2-ol

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Example 691-(2,3-dimethyl-1H-indol-1-yl)-3-(4-methoxyphenylamino)propan-2-ol

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Example 701-(2,3-dimethyl-1H-indol-1-yl)-3-(4-ethoxyphenylamino)propan-2-ol

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Example 71 1-(2,3-dimethyl-1H-indol-1-yl)-3-(p-tolylamino)propan-2-ol

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Example 72 1-(2,3-dimethyl-1H-indol-1-yl)-3-(phenylamino)propan-2-oloxalate

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Example 73 1-(1H-indol-1-yl)-3-(4-methoxyphenylamino)propan-2-olhydrochloride

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Example 74 1-(1H-indol-1-yl)-3-(phenylamino)propan-2-ol oxalate

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Example 751-(3,4-dihydro-1H-carbazol-9(2H)-yl)-3-(m-tolylamino)propan-2-ol

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Example 76 1-(9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol

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Example 77 1-(3,6-dichloro-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol

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Example 78 1-(9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol

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Example 79 1-(3,6-dichloro-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol

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Example 80 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol

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Example 81 N-(4-(3-(9H-carbazol-9-yl)-2-hydroxypropoxy)phenyl)acetamide

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Example 82 1-(9H-carbazol-9-yl)-3-phenoxypropan-2-ol

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Example 83 1-(9H-carbazol-9-yl)-3-(4-methoxyphenylamino)propan-2-ol

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Example 84 1-(benzylamino)-3-(9H-carbazol-9-yl)propan-2-ol

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Example 85 methyl 4-(3-(9H-carbazol-9-yl)-2-hydroxypropoxy)benzoate

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Example 86 1-(9H-carbazol-9-yl)-3-(4-methoxyphenoxy)propan-2-ol

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Example 87 1-amino-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol

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Example 88a (S)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol

Example 88b (R)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol

The title compounds of Examples 88a and 88b were prepared according tothe procedure described in Example 3b except using the appropriatecommercially available optically active phenoxymethyl oxirane as theepoxide starting material.

Example 89 3,6-dibromo-9-(2-fluoro-3-phenoxypropyl)-9H-carbazole

The title compound of Example 89 was prepared according to the proceduredescribed in Representative Procedure 4 except using the title compoundof Example 3b as the starting material. The crude mixture was purifiedin 100% DCM (+0.2% TEA). Isolated yield=97%.

¹H NMR (CDCl₃, 400 MHz) δ 8.13 (d, 2H, J=1.7 Hz), 7.51 (dd, 2H, J=8.7,1.9 Hz), 7.29-7.35 (m, 4H), 7.01 (t, 1H, J=7.5 Hz), 6.91 (d, 1H, J=7.8Hz), 5.16 (dddd, 1H, J=4.5, 5.4, 9.7, 46.0 Hz), 4.59-4.79 (m, 2H),4.03-4.17 (m, 2H).

MS (ESI), m/z: 519.9 [(M+HCOO)⁻; C21H16Br2FNO (M) requires 475.0].

Example 901-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-2-methylpropan-2-ol

Step 1. Chlorohydrin-19

m-Anisidine (0.18 mL, 1.62 mmol) was added to 2-chloromethyl-2-methyloxirane (0.154 mL, 1.62 mmol) in acetic acid (2 mL) and the mixture washeated to 75° C. Upon completion the reaction was neutralized withsaturated sodium bicarbonate to pH 7, then extracted 3× with EtOAc,washed with brine and dried with MgSO₄ filtered, and concentrated invacuo. The crude residue was purified by chromatography (SiO₂, 0-25%EtOAc/Hexane) to afford the desired alcohol (332 mg, 89%).

¹H NMR (CDCl₃, 400 MHz) δ 7.08 (t, 1H, J=8.1 Hz), 6.29 (m, 2H), 6.23 (t,1H, J=2.3 Hz), 3.95 (s, NH), 3.77 (s, 3H), 3.60 (dd, 2H, J=35.1, 11.0Hz), 3.25 (dd, 2H, J=44.8, 13.0 Hz), 2.31 (apparent d, OH), 1.36 (s, 3H)ESI m/z 230.1 ([M+H]⁺).

Step 2. Epoxide-20

Chlorohydrin-19 (0.166 g, 0.722 mmol) was dissolved in dioxane (1 mL)and added to a solution of KOH (0.168 mgs, 3.0 mmol). The reaction wasfollowed by TLC (20% EtOAc/Hexane) until the starting material wasconsumed and the less polar product was obtained. After aqueous workup,the crude product was used without purification.

¹H NMR (CDCl₃, 400 MHz) δ 7.07 (t, 1H, J=8.1 Hz), 6.27 (dd, 1H, J=8.2,0.8 Hz), 6.22 (dd, 1H, J=8.2, 0.8 Hz), 6.16 (t, 1H, J=2.3 Hz), 3.83 (s,NH), 3.32 (br s, 2H), 2.82 (d, 1H, J=4.5 Hz), 2.63 (d, 1H, J=4.5 Hz).

Reference: Chemistry of Heterocyclic Compounds volume 41, No 4, 2005, pg426.

Step 3

The title compound of Example 90 was prepared in 83% yield using3,6-dibromocarbazole, sodium hydride (NaH), and epoxide 20. See, e.g.,the procedure described in Example 21, step 4.

¹H NMR (CDCl₃, 400 MHz): δ 8.14 (s, 2H), 7.53 (d, 2H, J=8.9 Hz), 7.42(d, 2H, J=8.4 Hz), 7.09 (t, 1H, J=8.4 Hz), 6.33 (d, 1H, J=6.3 Hz), 6.27(d, 1H, J=6.3 Hz), 6.18 (s, 1H), 4.41 (d, 1H, J=15.3 Hz), 4.32 (d, 1H,J=15.3 Hz) 3.74 (s, NH), 3.49 (s, 3H), 3.28 (d, 1H, 12.4 Hz), 3.22 (d,1H, 12.4 Hz), 2.03 (s, OH), 1.33 (s, 3H) ESI m/z 518.9 ([M+H]⁺).

¹³C NMR (CDCl₃, 100 MHz) δ 161.0, 149.8, 140.6 (2C), 130.4 (2C), 129.4(2C), 123.8 (2C), 123.2 (2C), 112.8, 111.8 (2C), 106.9, 103.8, 99.8,75.0, 55.4, 52.5, 51.5, 25.1

ESI m/z 516.9 ([M+H]⁺, C₂₃H₂₂Br₂N₂O₂ requires 516.04

Example 911-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(3-methoxyphenylamino)propan-2-ol

Following a literature procedure (Zoidis, G.; Kolocouris, N.; Naesens,L.; De Clercq, E. Bioorg. Med. Chem. 2009, 17, 1534-1541), the titlecompound of Example 18 (0.015 g, 0.034 mmol) was dissolved in anhydrousTHF (0.34 mL) and cooled to 0° C. A solution of LAH (0.10 mL, 1.0 M inTHF) was added dropwise, and the reaction was stirred for 2 h at 0° C.MeOH was added to quench the remaining LAH and after 45 min, the mixturewas partitioned between EtOAc/H₂O. The organic layer was separated andthe aqueous layer was extracted with EtOAc (3×), and the combinedorganic layers were washed with satd. aq. NaCl, dried over Na₂SO₄,filtered, and concentrated. The crude residue was purified by columnchromatography (SiO₂, 0-20% MeOH/Acetone+1% Et₃N), followed by PTLC (10%MeOH/Acetone+1% Et₃N) to afford the desired product (0.6 mg, 5%).

¹H NMR (CDCl₃, 500 MHz) δ=7.14 (m, 2H), 7.04 (dd, 1H, J=8.0, 8.0 Hz),6.98 (d, 1H, J=8.5 Hz), 6.27 (d, 1H, J=8.0 Hz), 6.18 (d, 1H, J=8.0 Hz),6.12 (s, 1H), 4.14 (m, 1H), 4.10 (m, 1H), 4.01 (m, 1H), 3.72 (s, 3H),3.20 (m, 1H), 3.06 (m, 1H), 2.72 (s, 3H), 2.41 (s, 3H).

ESI m/z 380.2 ([M+H]⁺, C₂₃H₃₀N₃O₂ requires 380.2).

Example 921-(4-azidophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol

4-Azidoaniline (0.038 g, 0.283 mmol) was added to a solution of3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (0.100 g, 0.262 mmol) inTHF (0.10 mL). LiBr (0.001 g, 0.013 mmol) was added and the reaction wasstirred at room temperature for 3 days. The reaction was purifieddirectly by chromatography (SiO₂, 0-25% EtOAc/Hexane) to afford thedesired product (31 mg, 23%).

¹H NMR (d₆-acetone, 500 MHz) δ=8.36 (d, 2H, J=2.0 Hz), 7.61 (m, 2H),7.55 (m, 2H), 6.85 (m, 2H), 6.74 (m, 2H), 5.19 (br s, 1H), 4.61 (dd, 1H,J=4.0, 15.0 Hz), 4.56 (br s, 1H), 4.50 (dd, 1H, J=8.0, 15.0 Hz), 4.39(m, 1H), 3.39 (dd, 1H, J=4.5, 13.0 Hz), 3.25 (dd, 1H, J=6.5, 13.0 Hz).

¹³C NMR (acetone-d₆, 100 MHz) δ=147.7, 141.1, 129.8 (2C), 128.9, 124.5,124.0 (2C), 120.7 (2C), 114.9 (2C), 112.8 (2C), 112.6, 111.9, 69.6,48.5, 48.4.

ESI m/z 513.9 ([M+H]⁺, C₂₁H₁₈Br₂N₅O requires 514.0).

Example 931-(3-azido-6-bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol

Step 1. 3-azido-6-bromo-9H-carbazole

3,6-Dibromocarbazole (0.500 g, 1.538 mmol), NaN₃ (0.120 g, 1.846 mmol),CuI (0.029 g, 0.154 mmol), L-proline (0.053 g, 0.461 mmol) and NaOH(0.019 g, 0.461 mmol) were dissolved in 7:3 EtOH/H₂O (3.0 mL) and heatedto 95° C. under a N₂ atmosphere for 24 h. The completed reaction waspartitioned between EtOAc/H₂O (3×) and the combined organics were washedwith satd. aq. NaCl, dried over Na₂SO₄, filtered, and concentrated. Thecrude residue was purified by chromatography (SiO₂, 0-15%EtOAc/toluene), followed by HPLC (Phenomenex SiO₂ Luna 10 μL, 250×21.2mm column, 50% EtOAc/Hexane, 21 mL/min, retention time=48 min) to affordthe desired product.

¹H NMR (CDCl₃, 500 MHz) δ 8.14 (s, 1H), 8.08 (br s, 1H), 7.64 (s, 1H),7.50 (d, 1H, J=8.5 Hz), 7.38 (d, 1H, J=9.0 Hz), 7.29 (d, 1H, J=8.5 Hz),7.10 (d, 1H, J=9.0 Hz).

ESI m/z 285.0 ([M−H]⁻, C₁₂H₆BrN₄ requires 285.0).

Step 2

The Title Compound of Example 93 was Synthesized from3-azido-6-bromo-9H-carbazole in 46% yield using a procedure analogous tothat described in Example 90, step 3

¹H NMR (CDCl₃, 500 MHz) δ 8.14 (d, 1H, J=1.5 Hz), 7.64 (d, 1H, J=2.0Hz), 7.52 (dd, 1H, J=1.5, 8.5 Hz), 7.40 (d, 1H, J=9.0 Hz), 7.31 (d, 1H,J=8.5 Hz), 7.12 (dd, 1H, J=2.0, 8.5 Hz), 7.07 (dd, 1H, J=8.0, 8.0 Hz),6.31 (dd, 1H, J=2.0, 8.0 Hz), 6.21 (dd, 1H, J=1.5, 8.0 Hz), 6.13 (dd,1H, J=2.0, 2.5 Hz), 4.39-4.35 (m, 3H), 3.71 (s, 3H), 3.31 (dd, 1H,J=3.5, 13.0 Hz), 3.16 (dd, 1H, J=7.0, 13.0 Hz), 2.17 (br s, 1H).

ESI m/z 466.0 ([M+H]⁺, C₂₂H₂₁BrN₅O₂ requires 466.1).

Example 941-(3,6-dibromo-9H-carbazol-9-yl)-3-(4-methoxyphenoxy)propan-2-ol

The title compound of Example 93 was synthesized from dibromocarbazoleand (p-methoxyphenyl)-glycidyl ether in 47% yield using a procedureanalogous to those described in Example 90, step 3 and Example 93, step2.

¹H NMR (CDCl₃, 500 MHz) δ 8.12 (d, 2H, J=2.0 Hz), 7.50 (dd, 2H, J=2.0,8.5 Hz), 7.34 (d, 2H, J=8.5 Hz), 6.81 (m, 2H), 6.79 (m, 2H), 4.56 (m,1H), 4.42 (m, 3H), 3.93 (dd, 1H, J=4.5, 9.5 Hz), 3.81 (dd, 1H, J=4.5,9.5 Hz), 3.76 (s, 3H), 2.39 (d, 1H, J=6.0 Hz).

¹³C NMR (acetone-d₆, 100 MHz) δ 155.2, 153.8, 141.2 (2C), 129.8 (2C),124.5 (2C), 124.0 (2C), 116.4 (2C), 115.5 (2C), 112.9 (2C), 112.5 (2C),71.1, 69.8, 55.9, 47.4.

ESI m/z 547.9 ([M+CO₂H]⁻, C₂₃H₂₀Br₂NO₅ requires 548.0).

Example 951-(3,6-dichloro-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol

Step 1. 1-(3,6-dichloro-9H-carbazol-9-yl)-3-(phenylthio)propan-2-ol

The title compound of Example 95, step 1 was prepared using a procedureanalogous to that described in Example 3a (white solid, 0.0293 g, yield99.0%).

¹H NMR (CDCl₃, 400 MHz) δ=2.55 (s, 1H) 2.97 (dd, J=13.8, 7.2 Hz, 1H)3.09 (dd, J=13.9, 5.2 Hz, 1H) 4.20-4.06 (m, 1H) 4.28 (dd, J=15.0, 7.0Hz, 1H) 4.41 (dd, J=15.0, 4.1 Hz, 1H) 7.46-7.14 (m, 9H) 7.93 (d, J=1.8Hz, 2H)

¹³C NMR (CDCl₃, 400 MHz) δ=139.7, 134.5, 130.3, 129.5, 127.3, 126.8,125.4, 123.3, 120.4, 110.6, 69.3, 48.2, 39.4

ESI m/z: 446.0, 436.0 [(M+HCOO⁻), (M+Cl⁻); C21H17Cl2NOS (M) requires401.0].

Step 2

The title compound of Example 95 was prepared as follows. To a solutionof 1-(3,6-dichloro-9H-carbazol-9-yl)-3-(phenylthio)propan-2-ol (0.0081g, 0.0201 mmol) in 0.2 mL CH₂Cl₂, a solution of mCPBA (77%, 0.0113 g,0.0503 mmol) in 0.2 mL CH₂Cl₂ was added dropwise. The mixture was sealedand stirred at rt overnight. The crude was diluted with 30 mL EtOAc andwashed with saturated NaHCO₃ (3×30 mL) and brine 1×30 mL. The organiclayer was dried over anhydrous Na₂SO₄ and evaporated to afford the crudeproduct, which was subjected to silica gel chromatography usingHexanes/EtOAc to afford white solid as product (0.0080 g, yield 91.3%).

¹H NMR (CDCl₃, 400 MHz) δ=3.17 (dd, J=14.2, 3.0 Hz, 1H) 3.28 (dd,J=14.3, 8.3 Hz, 1H) 3.29 (d, J=2.9 Hz, 1H) 4.39 (d, J=6.3 Hz, 2H) 4.67(dtt, J=8.7, 5.9, 3.0 Hz, 1H) 7.31 (d, J=8.7 Hz, 2H) 7.40 (dd, J=8.7,2.0 Hz, 2H) 7.52 (t, J=7.9 Hz, 2H) 7.66 (t, J=7.5 Hz, 1H) 7.80 (d, J=7.3Hz, 2H) 7.96 (d, J=2.0 Hz, 2H).

¹³C NMR (CDCl₃, 400 MHz) δ=139.6, 138.8, 134.5, 129.8, 128.0, 127.0,125.7, 123.5, 120.5, 110.5, 65.8, 60.0, 48.5

ESI m/z: 477.9 [(M+HCOO⁻); C21H17Cl2NO3S (M) requires 433.0].

Example 963,6-dibromo-9-(2-fluoro-3-(phenylsulfonyl)propyl)-9H-carbazole

Step 1. 3,6-dibromo-9-(2-fluoro-3-(phenylthio)propyl)-9H-carbazole

The title compound of Example 96, step 1 was prepared by fluorination ofthe title compound of Example 31 using a procedure similar to thatdescribed in Representative Procedure 4.

¹H NMR (CDCl₃, 400 MHz) δ=3.09 (ddd, J=14.2, 11.3, 8.4 Hz, 1H) 3.37-3.23(m, 1H) 4.53 (ddd, J=20.8, 15.9, 6.7 Hz, 1H) 4.66 (ddd, J=26.6, 15.9,2.8 Hz, 1H) 5.04-4.81 (m, 1H) 7.36-7.27 (m, 5H) 7.42 (dt, J=3.2, 2.0 Hz,2H) 7.54 (dd, J=8.7, 1.9 Hz, 2H) 8.13 (d, J=1.9 Hz, 2H)

¹³C NMR (CDCl₃, 400 MHz) δ=139.8, 134.3, 129.6, 129.5, 127.6, 123.9,123.4, 112.9, 110.91 (d, J=2.1 Hz, 1C) 92.2, 90.4, 46.16 (d, J=22.8 Hz,1C) 35.63 (d, J=23.3 Hz, 1C)

Step 2

The title compound of Example 96 was prepared as follows. To a solutionof 3,6-dibromo-9-(2-fluoro-3-(phenylthio)propyl)-9H-carbazole (0.0143 g,0.0290 mmol) in 0.5 mL CH₂Cl₂, a solution of mCPBA (77%, 0.0162 g,0.0725 mmol) in 0.5 mL CH₂Cl₂ was added dropwise. The mixture was sealedand stirred at rt overnight. The crude was diluted with 30 mL EtOAc andwashed with saturated NaHCO₃ 3×30 mL and brine 1×30 mL. The organiclayer was dried over anhydrous Na₂SO₄ and evaporated to afford the crudeproduct, which was subjected to silica gel chromatography usingHexanes/EtOAc as elute to afford white solid as product (0.0114 g, yield74.8%).

¹H NMR (CDCl₃, 400 MHz) δ=3.61-3.40 (m, 2H) 4.56 (ddd, J=22.4, 16.0, 6.6Hz, 1H) 4.72 (dd, J=26.8, 15.9 Hz, 1H) 5.38 (dd, J=47.1, 5.9 Hz, 1H)7.34 (d, J=8.7 Hz, 2H) 7.63-7.53 (m, 4H) 7.68 (t, J=7.4 Hz, 1H) 7.90 (d,J=8.0 Hz, 2H) 8.12 (s, J=2.0 Hz, 2H)

¹³C NMR (CDCl₃, 400 MHz) δ=139.8, 134.7, 129.84, 129.79, 128.2, 124.1,123.5, 113.3, 110.91, 110.89, 88.1, 86.3, 58.4, 58.1, 47.3, 47.1

ESI m/z: 557.9 [(M+Cl⁻); C21H16Br2FNO2S (M) requires 522.9].

Example 97a(S)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol

Example 97b(R)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol

The title compounds of Examples 97a and 97b were prepared from (S)- or(R)-3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole using a proceduresimilar to that described in Example 3d.

Preparation of (S)-3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole[(S)-epoxide A]

To a solution of 3,6-dibromocarbazole (0.2194 g, 0.675 mmol) andtriphenylphosphine (0.1770 g, 0.675 mmol) in THF (5.4 mL) was addedS-(−)-glycidol (44.8 μL, 0.0500 g, 0.675 mmol). The reaction mixture wascooled in an ice bath and diethyl azodicarboxylate (106.3 μL, 0.1175 g,0.675 mmol) was added. The reaction mixture was allowed to warm to roomtemperature and stir overnight. THF was removed under vacuum and theresidue was dissolved in 30 mL EtOAc and washed with brine (3×30 mL).The organic layer was dried over anhydrous Na₂SO₄ and evaporated toafford the crude product, which was subjected to silica gelchromatography using Hexanes/EtOAc to afford white solid as product(0.0514 g, yield 20.0%).

Example 98 1-(3,6-dicyclopropyl-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol

Step 1. tert-butyl 3,6-dibromo-9H-carbazole-9-carboxylate

A solution of 3,6-dibromocarbazole (0.8288 g, 2.55 mmol) in 20 mL THFwas added to a suspension of NaH (60%, 0.1122 g, 2.81 mmol) in 10 mL THFat −78° C. After stirring for 1 h, a solution of (Boc)₂O anhydride(0.6122 g, 2.81 mmol) in 20 mL THF was added dorpwise into the mixture.The reaction was allowed to warm to room temperature and stir overnight.THF was removed under vacuum and the residue was dissolved in 30 mLEtOAc and washed with 1M HCl (2×30 mL) and brine (1×30 mL). The organiclayer was dried over anhydrous Na₂SO₄ and evaporated and the crudeproduct was subjected to silica gel chromatography using Hexanes/EtOActo afford white solid as product (0.9890 g, yield 91.7%).

¹H NMR (CDCl₃, 400 MHz) δ=1.75 (s, 9H) 7.58 (dd, J=8.9, 2.0 Hz, 1H) 8.05(d, J=1.8 Hz, 1H) 8.16 (d, J=8.9 Hz, 1H).

¹³C NMR (CDCl₃, 400 MHz) δ=150.5, 137.5, 130.5, 126.3, 122.6, 117.9,116.4, 84.9, 28.5.

Step 2. tert-butyl 3,6-dicyclopropyl-9H-carbazole-9-carboxylate

Following a literature procedure (Petit, S.; Duroc, Y.; Lame, V.;Giglione, C.; Leon, C.; Soulama, C.; Denis, A.; Dardel, F.; Meinnel, T.;Artaud, I. ChemMedChem 2009, 4, 261-275), tert-butyl3,6-dibromo-9H-carbazole-9-carboxylate (0.0200 g, 0.0470 mmol),cyclopropyl boronic acid (0.0202 g, 0.235 mmol), palladium acetate (10mol %, 0.0011 g, 0.00470 mmol), potassium phosphate tribasic (0.0350 g,0.165 mmol), tricyclohexylphosphine (0.0026 g, 0.00941 mmol), water(12.2 μL) and a stir bar were combined in a sealed vial. The vial wassparged with N₂ and charged with 0.22 mL degassed toluene. The mixturewas stirred at 100° C. for 65 h. The crude reaction mixture was dilutedwith 10 mL EtOAc and washed with brine (3×10 mL). The organic layer wasdried over anhydrous Na₂SO₄ and evaporated to afford the crude product,which was used as is without further purification.

¹H NMR (CDCl₃, 400 MHz) δ=0.82-0.76 (m, 4H) 1.02 (ddd, J=8.4, 6.4, 4.4Hz, 4H) 1.74 (s, 9H) 2.11-2.01 (m, 2H) 7.19 (dd, J=8.6, 1.9 Hz, 2H) 7.65(d, J=1.7 Hz, 2H) 8.14 (d, J=8.5 Hz, 2H)

Step 3. 3,6-dicyclopropyl-9H-carbazole

To a solution of the corresponding N-Boc carbazole (0.0163 g, 0.0469mmol) in 1 mL CH₂Cl₂, TFA (144.8 μL, 1.876 mmol) was added dropwise. Themixture was sealed and stirred at rt for 6 h. CH₂Cl₂ and TFA wereremoved under vacuum. The residue was diluted with 30 mL EtOAc andwashed with saturated NaHCO₃ 3×30 mL. The organic layer was dried overanhydrous Na₂SO₄ and evaporated to afford the crude product, which wassubjected to silica gel chromatography using Hexanes/EtOAc as elute toafford white solid as product (0.0139 g).

¹H NMR (CDCl₃, 400 MHz) δ=0.77 (dt, J=6.4, 4.5 Hz, 4H) 0.99 (ddd, J=8.4,6.2, 4.4 Hz, 4H) 2.13-2.03 (m, 2H) 7.16 (dd, J=8.4, 1.7 Hz, 2H) 7.28 (d,J=8.4 Hz, 2H) 7.76 (d, J=1.1 Hz, 2H) 7.83 (s, br, 1H).

Step 4. 3,6-dicyclopropyl-9-(oxiran-2-ylmethyl)-9H-carbazole

The title compound of Example 98, step 4 was prepared from3,6-dicyclopropyl-9H-carbazole using a procedure similar to thatdescribed in Representative Procedure 1.

¹H NMR (CDCl₃, 400 MHz) δ=0.81-0.74 (m, 4H) 1.03-0.96 (m, 4H) 2.09 (ddd,J=14.4, 8.9, 5.6 Hz, 2H) 2.53 (dd, J=4.8, 2.6 Hz, 1H) 2.77 (t, J=4.3 Hz,1H) 3.30 (dt, J=7.4, 3.9 Hz, 1H) 4.35 (dd, J=15.8, 4.6 Hz, 1H) 4.54 (dd,J=15.8, 3.4 Hz, 1H) 7.22 (dd, J=8.4, 1.7 Hz, 2H) 7.31 (d, J=8.4 Hz, 2H)7.78 (d, J=1.1 Hz, 2H).

Step 5

The title compound of Example 98 was prepared from3,6-dicyclopropyl-9-(oxiran-2-ylmethyl)-9H-carbazole using a proceduresimilar to that described in Representative Procedure 2.

¹H NMR (CDCl₃, 600 MHz) δ=0.79-0.75 (m, 4H) 0.99 (td, J=6.2, 4.6 Hz, 4H)2.08 (ddd, J=13.6, 8.5, 5.1 Hz, 2H) 3.21 (dd, J=12.9, 5.6 Hz, 1H) 3.35(d, J=13.8 Hz, 1H) 4.39 (s, J=23.7 Hz, 3H) 6.62 (d, J=8.4 Hz, 2H) 6.75(t, J=7.3 Hz, 1H) 7.17 (t, J=7.9 Hz, 2H) 7.20 (dd, J=8.4, 1.1 Hz, 2H)7.32 (d, J=8.4 Hz, 2H) 7.78 (s, 2H)

¹³C NMR (CDCl₃, 500 MHz) δ=148.2, 139.8, 134.9, 129.6, 124.8, 123.2,118.5, 117.5, 113.7, 108.8, 69.8, 48.0, 47.6, 15.7, 9.1

ESI m/z: 441.2 [(M+HCOO⁻); C₂₇H₂₈N₂₀ (M) requires 396.2].

Example 99 1-(3,6-diiodo-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol

Step 1. 3,6-diiodo-9-(oxiran-2-ylmethyl)-9H-carbazole

The title compound of Example 99, step 1 was prepared from 3,6-diiodocarbazole (Maegawa, Y.; Goto, Y.; Inagaki, S.; Shimada, T. TetrahedronLett. 2006, 47, 6957-6960) using a procedure similar to that describedin Representative Procedure 1.

¹H NMR (CDCl₃, 400 MHz) δ=2.48 (dd, J=4.6, 2.6 Hz, 1H) 2.80 (t, J=4.3Hz, 1H) 3.37-3.24 (m, 1H) 4.28 (dd, J=16.0, 5.1 Hz, 1H) 4.64 (dd,J=15.9, 2.7 Hz, 1H) 7.24 (d, J=8.6 Hz, 2H) 7.73 (dd, J=8.6, 1.6 Hz, 2H)8.33 (d, J=1.7 Hz, 2H)

¹³C NMR (CDCl₃, 500 MHz) δ=140.0, 135.0, 129.5, 124.3, 111.3, 82.6,50.6, 45.2, 44.9

Step 2

The title compound of Example 99 was prepared from3,6-diiodo-9-(oxiran-2-ylmethyl)-9H-carbazole using a procedure similarto that described in Representative Procedure 1.

¹H NMR (CDCl₃, 400 MHz) δ=2.92 (s, br, 1H) 3.19 (dd, J=12.8, 6.1 Hz, 1H)3.33 (d, J=10.9 Hz, 1H) 4.49-4.29 (m, 3H) 6.63 (d, J=8.3 Hz, 2H) 6.78(t, J=7.3 Hz, 1H) 7.20 (t, J=7.7 Hz, 2H) 7.28 (d, J=2.5 Hz, 2H) 7.72 (d,J=8.6 Hz, 2H) 8.35 (s, 2H).

¹³C NMR (CDCl₃, 400 MHz) 6=147.9, 140.1, 135.1, 129.65, 129.63, 124.4,118.9, 113.7, 111.5, 82.6, 69.6, 48.0, 47.3

ESI m/z: 613.0 [(M+HCOO⁻); C21H18I2N2O (M) requires 568.0].

Example 100 1-(3,6-diethynyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol

Step 1.1-(3,6-bis((triisopropylsilyl)ethynyl)-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol

The title compound of Example 62 (0.0112 g, 0.0222 mmol),bis(benzonitrile)dichloropalladium (3 mol %, 0.0003 g, 0.0007 mmol),[(tBu)₃PH]BF₄ (6.2 mol %, 0.0004 g, 0.0014 mmol), copper(I) iodide (2mol %, 0.0001 g, 0.0004 mmol), DABCO (0.0060 g, 0.0533 mmol) werecombined under an N₂ atmosphere. Degassed dioxane (0.1 mL) was added,and the resulting solution was stirred at room temperature for 10 min.Trimethylsilylacetylene (11.8 μL, 0.0533 mmol.) was added into themixture via microsyringe. The mixture was then stirred at rt overnight.The crude reaction mixture was diluted with 10 mL EtOAc and washed withbrine (3×10 mL). The organic layer was dried over anhydrous Na₂SO₄ andevaporated to afford the crude product, which was subjected to silicagel chromatography using Hexanes/EtOAc to afford colorless oil asproduct (0.0152 g, yield 96.8%).

¹H NMR (CDCl₃, 400 MHz) δ=1.22-1.13 (m, 42H) 2.24 (s, br, 1H) 3.17 (dd,J=12.6, 6.7 Hz, 1H) 3.31 (d, J=12.1 Hz, 1H) 3.71 (s, 3H) 4.48-4.31 (m,3H) 6.12 (t, J=2.1 Hz, 1H) 6.22 (dd, J=8.0, 1.8 Hz, 1H) 6.31 (dd, J=8.1,2.1 Hz, 1H) 7.07 (t, J=8.1 Hz, 1H) 7.37 (d, J=8.5 Hz, 2H) 7.58 (dd,J=8.5, 1.5 Hz, 2H) 8.22 (d, J=1.4 Hz, 2H)

¹³C NMR (CDCl₃, 400 MHz) 6=171.5, 161.0, 149.3, 140.9, 130.6, 130.4,124.9, 122.7, 115.1, 109.3, 108.2, 106.7, 103.9, 99.7, 88.7, 69.5, 55.3,47.4, 19.0, 11.6

Step 2

The title compound of Example 100 was prepared as follows. To a solutionof1-(3,6-bis((triisopropylsilyl)ethynyl)-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol(0.0152 g, 0.0215 mmol) in 200 μL anhydrous THF, a solution of TBAF inTHF (1 M, 64.5 μL, 0.0645 mmol) and acetic acid (2.5 μL, 0.0430 mmol)were added. The mixture was sealed and stirred under N₂ atmosphere at rtfor 27 h until TLC showed the complete disappearance of startingmaterial. The crude was diluted with 10 mL EtOAc and washed withsaturated NaHCO₃ (3×10) mL. The organic layer was dried over anhydrousNa₂SO₄ and evaporated to afford the crude product, which was subjectedto silica gel chromatography using Hexanes/EtOAc to afford white solidas product (0.0061 g, yield 71.9%).

¹H NMR (CDCl₃, 400 MHz) δ=2.24 (s, br, 1H) 3.09 (s, 2H) 3.20 (s, br, 1H)3.32 (s, br, 1H) 3.72 (s, 3H) 4.48-4.27 (m, 3H) 6.14 (s, 1H) 6.23 (dd,J=8.0, 1.4 Hz, 1H) 6.32 (dd, J=8.2, 1.8 Hz, 1H) 7.08 (t, J=8.1 Hz, 1H)7.40 (d, J=8.5 Hz, 2H) 7.59 (dd, J=8.5, 1.4 Hz, 2H) 8.21 (d, J=1.1 Hz,2H)

¹³C NMR (CDCl₃, 500 MHz) δ=161.1, 149.3, 141.2, 130.7, 130.4, 125.0,122.7, 113.6, 109.6, 106.7, 103.8, 99.8, 84.7, 76.0, 69.6, 55.3, 48.0,47.4

ESI m/z: 439.1 [(M+HCOO⁻); C26H22N2O2 (M) requires 394.2].

Example 1019-(2-hydroxy-3-(3-methoxyphenylamino)propyl)-9H-carbazole-3,6-dicarbonitrile

Following a literature procedure (Weissman, S. A.; Zewge, D.; Chen, C.J. Org. Chem. 2005, 70, 1508-1510), the title compound of Example 62(0.0252 g, 0.05 mmol), potassium hexacyanoferrate(II) trihydrate (0.0106g, 0.025 mmol), sodium bicarbonate (0.0106 g, 0.1 mmol) and palladiumacetate (1 mol %, 0.0001 g) were combined under a N₂ atmosphereAnhydrous dimethylacetamide (0.1 mL) was added, and the reaction mixturewas stirred at 120° C. overnight. The crude reaction mixture was dilutedwith 10 mL EtOAc and washed with water (2×10 mL) and brine (1×30 mL).The organic layer was dried over anhydrous Na₂SO₄ and evaporated toafford the crude product, which was subjected to silica gelchromatography using Hexanes/EtOAc to afford white solid as product(0.0110 g, yield 54.6%).

¹H NMR (d₆-acetone, 400 MHz) δ=2.81 (s, 1H) 3.36-3.28 (m, 1H) 3.50-3.43(m, 1H) 3.71 (s, 3H) 4.44 (s, br, 1H) 4.66 (dd, J=15.0, 8.5 Hz, 1H) 4.77(dd, J=15.1, 3.4 Hz, 1H) 5.16 (t, J=5.8 Hz, 1H) 6.22 (dd, J=8.1, 2.1 Hz,1H) 6.27 (t, J=2.0 Hz, 1H) 6.31 (dd, J=8.1, 1.2 Hz, 1H) 7.01 (t, J=8.1Hz, 1H) 7.84 (dd, J=8.6, 1.2 Hz, 2H) 7.91 (d, J=8.6 Hz, 2H) 8.74 (s, 2H)

¹³C NMR (d₆-acetone, 500 MHz) 6=161.3, 150.4, 143.9, 130.02, 129.95,126.0, 122.4, 119.8, 112.0, 106.0, 103.3, 102.5, 98.9, 69.0, 54.5, 48.0,47.7

ESI m/z: 441.1 [(M+HCOO⁻); C₂₄H₂₀N₄O₂ (M) requires 396.2).

Example 102 N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)aniline

Step 1.N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-nitro-N-phenylbenzenesulfonamide

The title compound of Example 102, step 1 was prepared from epoxide 2-Aand Ns-aniline using procedures similar to those described inrepresentative procedures 3 and 4. The crude mixture was purified in 40%EtOAc/hexanes (+0.1% TEA). The isolated yield was 60%.

¹H NMR ((CD₃)₂C0)₃, 400 MHz) δ 8.37 (m, 2H), 7.90 (m, 2H), 7.68 (m, 1H),7.53-7.60 (m, 6H), 7.32-7.40 (m, 5H), 5.03 (dm, 1H), 4.71-4.93 (m, 2H),4.27-4.41 (m, 2H).

MS (ESI), m/z: 703.9 [(M+HCOO)⁻; C27H20Br2FN3O4S (M) requires 659.0]

Step 2

The title compound of Example 102 was prepared as follows. Cesiumcarbonate (11.5 mg, 0.036 mmol), the nosylate prepared in step 1 above(7.9 mg, 0.012 mmol), THF (0.7 ml, 0.017 M) and benezenthiol (3.8 ul,0.037 mmol) were combined and stirred overnight. The crude reactionmixture was diluted with EtOAc, washed with water and brine. The organiclayer was dried over Na₂SO₄, filtered and condensed. Chromatographicpurification on SiO2(20% EtOAc/hexanes (0.2% TEA)) provided 74% (4.2mg).

¹H NMR (CDCl₃, 500 MHz) δ=8.16 (s, 2H), 7.56 (d, 2H, J=8.5 Hz), 7.31 (d,2H, J=8.5 Hz), 7.21 (t, 2H, J=7.4 Hz), 6.80 (t, 1H, J=7.3 Hz), 6.62 (d,2H, J=8.5 Hz), 5.11 (dddd, 1H, J=5.4, 5.4, 10.4, 47.4 Hz), 4.52-4.68 (m,2H), 3.94 (t, 1H, J=6.02 Hz), 3.30-3.51, (dm, 2H).

MS (ESI), m/z: 475.0 [(M+1)-; C21H17Br2FN2 (M) requires 474.0].

Example 103 3,6-dibromo-9-(2,2-difluoro-3-phenoxypropyl)-9H-carbazole

Step 1. 1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-one

Dess-Martin periodinane (58.2 mg, 0.137 mmol) was charged to a solutionof the title compound of Example 3b (45.0 mg, 0.095 mmol) indichloromethane (1.0 ml, 0.095 M). After two hours the reaction mixturewas diluted with EtOAc and washed with saturated sodium thiosulfatesolution, water and brine. The organic layer was dried over Na₂SO₄,filtered and condensed. The crude product was used without additionalpurification. Yield=74%

¹H NMR (CDCl₃, 400 MHz) δ 8.15 (d, 2H, J=1.9 Hz), 7.52 (dd, 2H, J=8.6,1.9 Hz) 7.35 (m, 2H), 7.08 (t, 1H, J=7.3 Hz), 7.04 (d, 2H, J=8.9 Hz),6.91 (m, 2H), 5.29 (s, 2H), 4.68 (m, 2H)

MS (ESI), m/z: 469.9 [(M−1)⁻; C21H15Br2NO2 (M) requires 570.9].

Step 2

The title compound of Example 103 was prepared as follows.Diethylaminosulfur trifluoride (39 ul, 0.30 mmol) was added dropwise toa solution of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-one(33.3 mg, 0.070 mmol) in anhydrous dichloromethane (1.5 ml, 0.047M). Thereaction was quenched with saturated sodium bicarbonate solution, andthen extracting three times with dichloromethane. The organic layer isdried over Na₂SO₄, filtered and condensed. The crude mixture waspurified on SiO2 (10% EtOAc/hexanes+0.2% TEA. Isolated yield was 69%.

¹H NMR (CDCl₃, 400 MHz) δ 8.09 (d, 2H, J=1.9 Hz), 7.48 (dd, 2H, J=8.7,1.8 Hz) 7.30-7.4 (m, 4H), 7.06 (t, 1H, J=7.3 Hz), 6.91 (d, 2H, J=7.9Hz), 4.79 (t, 2H, J=12.4 Hz), 4.07 (t, 2H, J=11.1 Hz).

MS (ESI), m/z: 537.9 [(M+HCOO)⁻; C21H15Br2F2NO (M) requires 492.9].

Example 104N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-methoxyaniline

Step 1.N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide

The title compound of Example 104, step 1 was prepared from epoxide 2-Aand Ns-anisidine according to Representative Procedure 3. Yield=71%

¹H NMR (CDCl₃, 400 MHz) δ 8.29 (d, 2H, J=8.7 Hz), 8.11 (d, 2H, J=1.9Hz), 7.71 (, 2H, J=8.6 Hz), 7.52 (dd, 2H, J=8.6, 1.9 Hz), 7.23 (d, 2H,J=8.9 Hz), 6.94 (d, 2H, J=8.9 Hz), 6.82 (d, 2H, J=8.9 Hz), 4.44 (dd, 1H,J=14.8, 3.8 Hz), 4.30 (m, 1H), 4.21 (bs, 1H), 3.81 (s, 3H), 3.69 (m,2H).

MS (ESI), m/z: 732.0 [(M+HCOO⁻); C₂₈H₂₃Br₂N₃O₆S (M) requires 687.0]

Step 2.N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide

The title compound of Example 104, step 2 was prepared from the nosylateprepared in step 1 above according to General Procedure 4. Yield=61.5%

¹H NMR (CDCl₃, 400 MHz) δ 8.27 (m, 2H), 8.09 (m, 2H), 7.71 (d, 2H,J=7.41 Hz), 7.53 (m, 2H), 7.19 (m, 2H), 6.95 (d, 2H, J=8.8 Hz), 6.82 (d,2H, J=8.8 Hz), 4.92 (dm, 1H, J_(d)=48.3 Hz), 4.55 (m, 2H), 3.88 (m, 2H),3.79 (s, 3H).

MS (ESI), m/z: 734.0 (M+HCOO)⁻; C₂₈H₂₂Br₂FN₃O₅S (M) requires 689.0]

Step 3

The title compound of Example 104 was prepared according toRepresentative Procedure 5. Isolated yield 70%.

¹H NMR (CDCl₃, 400 MHz) δ 8.14 (m, 2H0, 7.53 (dt, 2H, J=8.8, 1.6 Hz),7.30 (d, 2H, 8.6 Hz), 6.78 (d, 2H, J=7.9 Hz), 6.57 (d, 2H, J=7.9 Hz),5.07 (dddd, 1H, J=4.7, 6.1, 9.4, 47.7), 4.58 (m, 2H), 3.75 (s, 3H), 3.32(m, 2H).

MS (ESI), m/z: 549.0 [(M+HCOO)⁻; C22H19Br2FN2O (M) requires 505.0).

Example 105N-(2-bromo-3-(3,6-dibromo-9H-carbazol-9-yl)propyl)-N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide

Step 1.N-(2-bromo-3-(3,6-dibromo-9H-carbazol-9-yl)propyl)-N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide

A solution of the title compound Example 104 (20.5 mg, 0.030 mmol) inanhydrous dichloromethane (1.0 ml, 0.03 M) was cooled in an ice bathbefore the addition of BBr₃ (7 ul, 0.074 mmol). After 1 h the reactionwas diluted with EtOAc, washed twice with water, saturated sodiumbicarbonate solution and brine. The organic layer was dried over Na₂SO₄,filtered and condensed. The crude mixture was purified in 100% CH₂Cl₂(+0.2% TEA). Isolated yield=56%

¹H NMR (CDCl₃, 500 MHz) δ 8.26 (d, 2H, J=8.9 Hz), 8.12 (d, 2H, J=1.7Hz), 7.60 (d, 2H, J=8.8 Hz) 7.53 (dd, 2H, J=8.7, 1.9 Hz), 7.18 (d, 2H,J=8.7 Hz), 6.89 (d, 2H, J=8.9 Hz) 6.81 (d, 2H, J=9.0 Hz), 4.86 (dd, 1H,J=15.6, 5.4 Hz), 4.57 (m, 1H), 4.44 (m, 1H), 3.92 (m, 2H), 3.82 (s, 3H)

MS (ESI), m/z: 747.9 [(M−1)⁻; C28H22Br3N3O5S (M) requires 748.9]

Step 2

The title compound of Example 105 was prepared from the nosylateprepared in step 1 above according to Representative Procedure 5.Isolated yield=43% in approximately 90% purity.

¹H NMR (CDCl₃, 400 MHz) δ 8.14 (d, 2H, J=1.7 Hz), 7.51 (dd, 2H, J=8.6,1.9 Hz), 7.28 (d, 2H, J=8.7 Hz), 6.71 (d, 2H, J=8.9 Hz), 6.41 (d, 2H,J=8.8 Hz), 4.84 (m, 1H), 4.63 (m, 3H), 3.82 (m, 1H), 3.73 (s, 3H)

MS (ESI), m/z: 564.8 [(M+1)⁺; C22H19Br3N2O requires 563.9].

The title compounds of Examples 106-109 can be prepared using themethods described herein and/or using conventional synthesis methods.

Example 106 Ethyl2-(4-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropylamino)phenoxy)acetate

Example 107N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-(2-(2-methoxyethoxy)ethoxy)aniline

Example 108

Example 109

Compounds were tested in vivo for dose-responsive neurotrophic efficacy.The results are shown in Table 1.

TABLE 1 In Vivo Activity (X10⁻⁰⁶) BrdU+ cells/mm³ SEM: (standard errorof Test Material dentate gyrus the mean) Vehicle 14.5 1.08 FGF-2:(fibroblast growth 28.4 2.12 factor 2) Example 1a 29.8 2.0 Example 1b18.3 0.8 Example 2 24.4 1.4 Example 3a 30.9 3 Example 3b 29.6 1.3Example 3c 16.1 1.74 Example 3d 27.1 1.34 Example 4 23.7 0.6 Example 521.5 2.18 Example 6a 38 2.4 Example 6b 25.5 (one animal tested) Example7a 18.4 1.8 Example 7b 23.4 1.31 Example 8 23.2 0.8 Example 9 16.2 1.7Example 10 27 1.3 Example 11 15.1 0.6 Example 12 21.7 2.9 Example 1328.5 2.6 Example 14 17.8 1.9 Example 15 15.1 0.9 Example 16 17.1 0.9Example 17 20.8 0.3 Example 19 15 0.5 Example 20 23.2 0.48 Example 2127.6 3.4 Example 22 27.3 1.8 Example 23 21.5 2.2 Example 25 16.8 1.3Example 26 15.6 1 Example 28 21 0.6 Example 29 17.6 2.3 Example 30 13.41.2 Example 31 14.7 1 Example 32 16 0.4 Example 33 14 0.2 Example 36 192.54 Example 39 23.4 1.1 Example 40 14.4 1.5 Example 41 16 1.1 Example43 21.3 2.6 Example 45 30 1.42 Example 88a 16.2 1 Example 88b 30.6 3.66Example 89 23.4 0.26 Example 90 33.3 3.3 Example 91 18.3 2.9 Example 9229 1.6 Example 93 20.1 2.5 Example 94 23.9 2.43 Example 95 21.5 1.2Example 96 34.2 4.29 Example 97a 32.4 3.84 Example 97b 26.3 1.55 Example101 25.8 2.6 Example 102 27.6 2.7 Example 103 16.8 1.13 Example 104 25.12

25.4 2.4 Example 109 23.7 0.75 Compounds were evaluated forpro-neurogenic efficacy/neuroprotection in our standard in vivo assay at10 μM concentration in four 12 week old adult male C57/B16 mice.

The (+) (dextrorotatory) enantiomer of1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol asdescribed herein exhibited high activity.

The (−) (levorotatory) enantiomer of1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol asdescribed herein exhibited low activity.

Identification of Pro-Neurogenic or Neuroprotective Compounds:

In an effort to identify compounds that might stimulate the birth of newneurons, or protect newborn neurons from cell death, a library of 1,000compounds was screened using an in vivo assay. In the initial screen,compounds were randomly pooled into groups of ten and administeredintracerebroventricularly at a constant rate over seven days into theleft lateral ventricle of living mice via Alzet osmotic mini-pumps.Compounds were administered at a concentration of 10 μM for eachmolecule, making a total solute concentration of 100 μM. After sevendays of infusion at a constant rate of 0.5 μL/hour, a total of 84 μL ofvolume will have left the pump (0.00084 μMoles) and entered thecerebrospinal fluid. The average volume of a brain from a 12 week oldmale, C57/B6 mouse in our study is 500 mm³. The maximal amount of drugwas estimated that could potentially be present in the brain, taking theextreme and unlikely scenario of 100% absorbance of the drug into braintissue and 0% clearance throughout the seven day infusion period. Underthese conditions, at the end of one week of infusion each compound wouldbe present at 1.7 μMolar concentration. Since the actual amount ofchemical compound in the brain is likely to be only a fraction of thispredicted level, it is reasonable to estimate that compounds wereadministered at mid to low-nanomolar concentrations.

During compound infusion, animals were intraperitoneally (IP) injecteddaily with the thymidine analog, bromodeoxyuridine (BrdU), as a means ofscoring the birth and survival of proliferating neural precursor cellsin the hippocampus. Because both social interaction and voluntaryexercise are known to stimulate hippocampal neurogenesis, mice werehoused individually without access to running wheels throughout thescreening period. Following the week-long period of compoundadministration, animals were perfused and sacrificed. Dissected braintissue was fixed, embedded, sectioned, stained with antibodies to BrdU,and evaluated by light microcopy as a means of quantifying neurogenesisand survival of newborn neural precursor cells localized to thesubgranular layer of the dentate gyms on the brain hemispherecontralateral to the side of mini-pump cannulation. Every fifth sectionthroughout the entire rostral-caudal extent of the hippocampus wasanalyzed, and the total number of BrdU+ cells was normalized against themeasured volume of the dentate gyms. Because both increasedproliferation and survival of newborn neurons are important screeningparameters, the screen was conducted over seven days in order to cast awide net to detect molecules that might augment either process. Thechoice of parameters for the screen was based on pulse-chase experimentswith a single injection of BrdU, under identical conditions to thoseused in our screen, which revealed that 40% of newborn cells in thedentate gyms die within the first five days of their birth (FIG. 1).Intracranial infusions of either fibroblast growth factor 2 (FGF-2) orartificial cerebral spinal fluid (aCSF) vehicle via the same, week-longprotocol were employed as positive and negative controls. There was nodifference in the number of BrdU-labeled cells in the dentate gymsbetween mice subjected to surgical pump implantation and infusion withvehicle, and mice having had no surgery (FIG. 2). This confirmed thevalidity of the in vivo approach to assess the ability ofintracerebroventricularly infused compounds to enhance hippocampalneurogenesis in the contralateral hemisphere.

We considered it to be important that stimulation of neurogenesistriggered by any compound be localized to the exact region of the brainknown to produce new neurons at an enhanced level in response to healthyactivities such as wheel running, access to an enriched environment, oraccess to social interaction. For this reason attention was focusedsolely on compound pools that stimulated BrdU incorporation only in thesubgranular zone of the dentate gyms. Prominent nonspecificincorporation of BrdU in ectopic regions, such as CA3, CA1, cortex, orstriatum, was presumed to reflect pathological inflammation, asproliferating cells incorporate BrdU in DNA synthesis, or to indicateother forms of toxicity, as cells also incorporate BrdU during DNArepair. Any compound pools yielding ectopic BrdU incorporation wereeliminated from the screen. For an example, see FIG. 3.

Each of the 100 pools was tested on two independent mice. As shown inFIG. 4, ten of the 100 test pools were observed to enhance dentategyms-specific neurogenesis to an extent roughly equivalent to FGF-2.Each pool that scored positive in the initial two test animals wassubsequently re-evaluated in two additional mice, and all ten pools werefound to exert their pro-neurogenic effect with statistical significance(FIG. 5). In order to identify single, pro-neurogenic compounds,positive pools were broken down into their ten component molecules, eachof which was infused individually at two concentrations (10 μM and 100μM) in two mice per concentration. FIG. 6A shows the results ofbreak-down assays on pool #7, wherein it was discovered thatneurogenesis was selectively stimulated by one of the constituentchemicals of the pool (compound #3), chemicals in the pool demonstratingno effect. We designate this molecule as Example 45 Compound. Inbreaking down the ten positive pools, eight pools yielded a singlepro-neurogenic compound (FIG. 6B). To ensure that the pro-proliferativeor neuroprotective effect on neural stem cells was not an artifact ofstorage conditions in the UTSWMC chemical compound library, re-suppliedcompounds were verified to by 99% pure by mass spectrometry, evaluatedin 4 mice each at 10 μM concentration, and shown to retain eitherpro-proliferative or neuroprotective properties in neural stem cells(FIG. 6C).

Pharmacokinetic analysis of Example 45 Compound in plasma and wholebrain tissue was undertaken after single IV, IP and oral gavageadministrations. Example 45 Compound was noted to be orallybioavailable, readily able to cross the blood-brain barrier, and endowedwith a plasma terminal half life of 6.7 hours after IP delivery. Thesefavorable pharmacological properties facilitated a dose responseexperiment wherein daily oral administration of Example 45 Compound toadult mice was monitored for both brain levels of the chemical andpro-neurogenic efficacy (FIG. 7). Maximal, pro-neurogenic efficacy wasobserved at oral doses of 5 mg/kg and above, and graded reductions inefficacy were observed at doses of 2.5 and 1 mg/kg. Liquidchromatography-mass spectrometry analysis of the brain levels of Example45 Compound in the dose ranges of 1, 2.5 and 5 mg/kg revealedcorresponding compound concentrations of 213 nM (101 ng/g brain tissue),1.13 μM (534 ng/g brain tissue) and 1.35 μM (640 ng/g brain tissue) fivehours after dosing.

Enantiomer Selective Activity of Example 45 Compound Derivative 62:

In order to further study Example 45 Compound, an in vivo structureactivity relationship (SAR) study was conducted using 37 chemicalderivatives of the compound for pro-neurogenic activity via directadministration into the brain of adult mice via Alzet minipumps.Compounds were administered for one week at 10 uM into 4 mice percompound, along with daily IP injections of BrdU. Following compoundadministration, animals were perfused, sacrificed and subjected tosectioning, staining and light microscopy in order to monitorhippocampal neurogenesis localized to the subgranular layer of thedentate gyms. Roughly 10% of the variant compounds retainedpro-neurogenic activity indistinguishable from the parent compound. Anapproximately equal number of compounds yielded slightly diminishedactivity, yet the majority of variants were of significantly diminishedactivity (FIG. 8). A variant of Example 45 Compound having a methoxysubstitution on the aniline ring (Example 62 Compound) was re-tested forpro-neurogenic activity via direct administration into the brain ofadult mice via Alzet minipumps. The compound was administered for oneweek at 10 μM into 4 mice which were injected daily with BrdU. Followingcompound administration, animals were perfused, sacrificed and subjectedto sectioning, staining and light microscopy in order to monitorhippocampal neurogenesis localized to the subgranular layer of thedentate gyms. The methoxy derivative exhibited activity comparable toExample 45 Compound. Subsequently, the (+) and (−) enantiomers ofExample 62 Compound were prepared (FIG. 9A). The two enantiomers wereevaluated in the in vivo neurogenesis assay. The (+)-enantiomer ofExample 62 Compound retained potent pro-neurogenic activity, and the (−)enantiomer displayed diminished activity (FIG. 9B).

Example 45 Compound Enhances the Survival of Newborn Neurons

The nature of the cells produced in the subgranular zone of the dentategyms was investigated when Example 45 Compound was administered asfollows. Animals were exposed to oral administration of Example 45Compound for 30 days. Brain tissue was then prepared forimmunohistochemical staining with an antibody to doublecortin (DCX), amicrotubule-associated protein that serves as a marker of neurogenesisin the dentate gyms by virtue of transient expression in newly formedneurons, but not glial cells, between the timing of their birth andfinal maturation (Brown et al., 2003). As shown in FIG. 10A, therelative abundance of doublecortin-positive neurons increaseddramatically as a function of exposure to prolonged administration ofExample 45 Compound. Although this observation does not rule out thepossibility that the compound might also enhance the formation of glialcells, it clearly shows that Example 45 Compound enhanced the formationof cells destined to become neurons.

Example 45 Compound-mediated neurogenesis was next investigated to seewhether it was attributable to increased cell proliferation orprotection of newborn cells from cell death during the time betweentheir birth and eventual incorporation into the granular layer of thedentate gyms. This was accomplished by comparing the ability of Example45 Compound to enhance either short- or long-term increases in theincorporation of BrdU in the dentate gyms (FIG. 10B). Animals exposed toorally-delivered Example 45 Compound or vehicle for 30 days wereadministered a single pulse of BrdU via IP injection. Short-term effectson neuron birth were monitored by sacrificing animals one hour post-BrdUinjection, followed by fixation of the tissue, sectioning andimmunohistochemical detection of BrdU incorporation into cells localizedin the subgranular layer of the dentate gyms.

Example 45 Compound administration did not lead to an elevation in thelevel of BrdU-positive cells relative to vehicle in this short-termassay. At one day after BrdU administration both groups still showed nostatistically significant differences in number of BrdU+ cells in thedentate gyms. By contrast, at the 5 day time point, by which time 40% ofnewborn cells in our assay normally die (FIG. 1), animals that receivedExample 45 Compound showed a statistically significant, 25% increase inBrdU+ cells compared to the vehicle-only control group. This differencebetween groups progressed with time such that mice that received a dailyoral dose of Example 45 Compound for 30 days starting 24 hours after thepulse treatment of BrdU exhibited a 5-fold increase in the abundance ofBrdU-positive cells in the dentate gyms relative to vehicle-onlycontrols. Notably, in this longer-term trial, BrdU-positive cells wereobserved not only along the subgranular layer of the dentate gyms wherenew neurons are known to be born, but also within the granular layeritself We hypothesize that these cells represent mature neurons thathave migrated into the granular layer, completed the differentiationprocess, and incorporated themselves into the dentate gyms as properlywired neurons. Observations supportive of this interpretation will bepresented in a subsequent section of this document. In summary, theseexperiments give evidence that Example 45 Compound enhances theformation of neurons in the mature hippocampus, and that its mode ofaction would appear to take place at some point subsequent to theirbirth.

Example 45 Compound Normalizes Apoptosis and Ameliorates Morphologicaland Electrophysiological Deficits in the Dentate Gyrus ofNPAS3-Deficient Mice

Mice lacking both copies of the gene encoding neuronal PAS domainprotein 3 (NPAS3) suffer a profound impairment in adult neurogenesis(Pieper et al., 2005). By evaluating BrdU incorporation in a short-termassay of neurogenesis by sacrificing animals 1 hours after BrdU pulse,it was observed that NPAS3-deficient animals have no detectable deficitin the birth of neurons in the subgranular layer of the dentate gyms(FIG. 11). This is in contrast to our earlier observations of profoundlydiminished BrdU labeling in the dentate gyms of NPAS3-deficient animalswhen BrdU is administered for a longer period of time (12 days) (Pieperet al., 2005). Knowing that the NPAS3 transcription factor is requiredfor proper expression of the fibroblast growth factor receptor 1 (FGFR1)in the hippocampus (Pieper et al., 2005), it is possible thatimpediments in growth factor signaling might impair the trophicenvironment critical for the survival of newborn neurons in the dentategyms. As an initial test of this hypothesis, brain tissue prepared fromNPAS3-deficient animals was compared with that of wild type littermatesfor the presence of cleaved caspase 3 (CCSP3)-positive cells in thesubgranular layer of the dentate gyms. A statistically significant,2-fold increase in CCSP3-positive (apoptotic) cells was observed in thedentate gyms of NPAS3-deficient animals (FIG. 11). This enhanced rate ofprogrammed cell death is likely to account, at least in part, for thenearly complete elimination of adult neurogenesis in mice lacking theNPAS3 transcription factor (Pieper et al., 2005).

In addition to this quantitative deficit in adult neurogenesis, we haveobserved abnormalities in both the morphology and electrophysiology ofgranular neurons of the dentate gyms of NPAS3-deficient animals.Relative to wild type animals, Golgi-Cox staining revealed severeattenuation in dendritic branching and spine density of dentate gymsgranular neurons of NPAS3-deficient animals (FIGS. 12 a and 12 b). Bycontrast, no genotype-dependent differences in these measures wereobserved in pyramidal cells of the CA1 region of the hippocampus.Equivalently specific deficits were observed by electrophysiologicrecordings of NPAS3-deficient animals compared with wild typelittermates (FIGS. 13 a and 13 b). Whole field recordings of excitatorypostsynaptic potentials (fEPSP) revealed significant deficits inNPAS3-deficient animals, relative to wild type littermates. In thedentate gyms, stimulating and recording electrodes were positioned inthe outer molecular layer, which is innervated by axons of the perforantpathway originating from the entorhinal cortex. In the CA1 region of thehippocampus, stimulation and recording electrodes were positioned in thestratum radiatum, which is innervated by the Schaffer collateral axonsof CA3 pyramidal cells. Stimulus intensity was increased in 5 μAincrements, the slope of the decreasing part of field potentials wasmeasured, and fEPSP was quantified relative to the amplitude of thefiber volley, which represents firing of action potentials inpre-synaptic axons. This analysis revealed aberrant hyper-excitabilityof synaptic transmission in npas3^(−/−) mice both in the outer molecularlayer of the dentate gyms and in the CA1 region (FIGS. 13 a and 13 b).

Armed with these genotype- and region-specific deficits in both neuronmorphology and electrophysiological activity, we set out to test whetherprolonged administration of Example 45 Compound might favorably repaireither deficit in NPAS3-deficient animals. Before embarking on thiseffort, we first confirmed that Example 45 Compound was capable ofenhancing hippocampal neurogenesis in NPAS3-deficient mice, bydemonstrating that Example 45 Compound enhances both BrdU incorporationas well as expression of doublecortin in newborn neurons in the dentategyms of npas3^(−/−) mice (FIG. 14). Knowing that formation of thedentate gyms initiates in the late pre-natal mouse embryo aroundembryonic day 14 (Stanfield and Cowan, 1988), we sought to exposeanimals to Example 45 Compound for as extended a period of time aspossible in order to give the compound the best possible chance forexhibiting favorable effects. Following oral gavage of pregnant femalemice, 14 day embryos were recovered, dissected and processed byacetonitrile:water extraction so that Example 45 Compound levels couldbe measured in the embryonic brain. Daily administration of 20 mg/kg ofExample 45 Compound to pregnant females yielded appreciable levels ofthe compound in the brain tissue of developing embryos. It was similarlyobserved that oral administration of the compound to lactating femalesled to delivery of Example 45 Compound to the brain tissue of weanlingpups. In both cases, LC/MS-based quantitation of Example 45 Compoundrevealed levels of compound accumulation at or above the 1.35 μM limitrequired to support adult neurogenesis (FIG. 7). Finally, it wasobserved that daily IP administration of Example 45 Compound to weanedpups at 20 mg/kg was sufficient to yield brain levels of Example 45Compound at or above the level required to enhance adult neurogenesis.

Female mice heterozygous at the NPAS3 locus were mated to heterozygousmales. Two weeks post-mating, females were given a daily oral gavage ofeither 20 mg/kg of Example 45 Compound or vehicle-only formula. Dosingwas continued throughout the last trimester of pregnancy, as well as thetwo week post-natal period of lactation. Following weaning, pups weregiven a daily IP dose of either 20 mg/kg Example 45 Compound or vehiclecontrol. At about 7 weeks of age, mice were switched to oral gavagedelivery of the same dose of Example 45 Compound. When mice were 3months of age they were sacrificed and brain tissue was dissected andsubjected to either Golgi-Cox staining or electrophysiologicalrecording. As shown in FIG. 15, prolonged exposure to Example 45Compound robustly repaired morphological deficits in the dendriticbranching of granular neurons of the dentate gyms in NPAS3-deficientmice. Moreover, as shown in FIG. 13A, the electrophysiological deficitin the dentate gyms of NPAS3-deficient mice was also corrected followingprolonged exposure of mice to Example 45 Compound. The correspondingelectrophysiological deficit in CA1 region of the hippocampus, however,was not affected (FIG. 13B), underscoring the specificity of Example 45Compound to improving functioning of the dentate gyms in this animalmodel.

It is also notable that, relative to vehicle-only controls,administration of Example 45 Compound did not affect any aspect of thehealth of mothers, embryos, weanlings or young adult mice. Grosshistology of brain tissue was normal in both compound- andvehicle-treated animals, and there was no evidence of neuronal cell lossor degenerative changes (cytoplasmic eosinophilia, vacuolization ornuclear pyknosis). The only morphological change, other thannormalization of dendritic arborization of granular neurons of thedentate gyms, was a compound-dependent increase in the thickness of thegranular layer of the dentate gyms itself (FIG. 16). The thickness ofthe granular layer of the dentate gyms is roughly 40% less inNPAS3-deficient animals than wild type littermates. Prolongedadministration of Example 45 Compound through late embryonicdevelopment, early post-natal development, and two months post-weaningsignificantly corrected this deficit without affecting the thickness ofother hippocampal layers in NPAS3-deficient mice (FIG. 16).

Recognizing that the reduced thickness of the granular layer of thedentate gyms in NPAS3-deficient animals could be attributed to elevatedlevels of apoptosis of newborn hippocampal neural precursor cells, weexamined the effect of Example 45 Compound treatment on apoptosis in thehippocampus of NPAS3-deficient animals through immunohistochemicalstaining of cleaved caspase 3 (CCSP3). As shown in FIG. 17, 12 days oftreatment with orally delivered Example 45 Compound (20 mg/kg) to adultNPAS3-deficient animals significantly reduced CCSP3 staining in thedentate gyms, whereas vehicle-treatment had not effect. We therebypropose that Example 45 Compound facilitated repair of the granularlayer of the dentate gyms in NPAS3-deficient mice by ameliorating agenotype-specific exacerbation of programmed cell death.

Example 45 Compound Protects Cultured Cortical Neurons from Beta-AmyloidToxicity

Apoptosis is implicated in numerous neurodegenerative disorders, and wewondered if Example 45 Compound might protect mature neurons fromprogrammed cell death. Cultured primary cortical neurons have been shownto undergo apoptosis following exposure to β-amyloid peptide (Loo etal., 1993). Accordingly, we investigated whether Example 45 Compoundmight protect cultured neurons from this paradigm of cell death.Cortical neurons from embryonic day 18 rats were allowed to mature for 1week, exposed to 25 μM A β₍₂₅₋₃₅₎ peptide fragment for 48 hours, andthen assayed for cell viability by light microscopic visualization aswell as the cell titer blue viability assay (Promega), which utilizesthe indicator dye resazurin to measure the metabolic activity ofcultured cells. As shown in FIG. 18, Example 45 Compound protectedcultured primary cortical neurons from A β₍₂₅₋₃₅₎-mediated toxicity.Dose response testing revealed that Example 45 Compound did not losemaximal neuroprotective activity even when diluted to low nanomolarlevels. Importantly, when the (+) and (−) enantiomers of the methoxyderivative of Example 45 Compound (Example 62 Compound) were tested,neuroprotective activity was observed with the same (+) enantiomer ofExample 62 Compound that also retained pro-neurogenic activity in livingmice, while the (−) enantiomer again displayed diminished activity

Example 45 Compound Acts in Mitochondria to Protect MitochondrialIntegrity

In order to investigate its cellular site of action, example 62 compoundwas modified by attaching a coumarin moiety to the N-phenyl ringaccording to established methods (Alexander et al., 2006), yielding afluorescent derivative designated FASDP (fluorescent, anisidinesubstituted derivative of Example 45 Compound) (FIG. 19). FASDP wasconfirmed to retain pro-neurogenic activity in adult mice in ourstandard assay, and cultured osteoblast cells were exposed to FASDP andvisualized by fluorescence optics in a light microscope. As shown inFIG. 20, FASDP labeled cells in a punctuate pattern that overlapped withmitochondria as visualized by Mitotracker dye. These observations areconsistent with the hypothesis that the activity and molecular target ofExample 45 Compound may reside within mitochondria.

Extensive evidence pioneered by the laboratory of Xiaodong Wang hasshown that an intrinsic pathway leading to programmed cell deathemanates from mitochondria (Liu et al., 1996; Yang et al., 1997). Withthe help of the Wang lab, assays were established to test whetherExample 45 Compound might protect mitochondria from calcium-induceddissolution (Distelmaier et al., 2008). Tetramethylrhodamine methylester (TMRM) is a cell-permeant, cationic red-orange fluorescent dyethat is readily sequestered by active mitochondria. When loaded withTMRM dye, vehicle-only treated cells released the dye within 15 minutesof exposure to the calcium ionophore A23187. By contrast, dye releasewas prevented in cells exposed to as little as 10 ng of Example 45Compound (FIG. 21A). As with in vivo neurogenesis assay, as well as thein vitro protection from Aβ₍₂₅₋₃₅₎-mediated toxicity of culturedcortical neurons, preservation of mitochondrial membrane potential inthis assay was observed only with the (+) enantiomer of Example 62Compound (FIG. 21B).

Comparison of Example 45 Compound and Dimebon

A chemical compound sharing structural similarity to Example 45 Compoundis2,3,4,5-Tetrahydro-2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-1H-pyrido(4,3-b)indole(FIG. 22A). An anti-histamine, trade named Dimebon, was anecdotallynoticed over the decades to ameliorate symptoms of dementia (O'Brien,2008; Burns and Jacoby 2008). More recently, an American biotechnologycompany designated Medivation initiated clinical trials to formally testwhether Dimebon might improve the symptoms of patients suffering fromAlzheimer's disease. The results of FDA-sponsored, phase 2 clinicaltrials in Alzheimer's disease were recently published, reportingfavorable response rates (Doody et al., 2008). Example 45 Compound andDimebon were compared in three functional assays. The in vivo test foreffects on hippocampal neurogenesis revealed activity for bothcompounds, with Example 45 Compound exhibiting between 10- and 30-foldhigher level of potency and a ceiling of efficacy roughly 40% higherthan the anti-histamine drug (FIG. 22 b). Dimebon has previously beenreported to protect cortical neurons from Aβ₍₂₅₋₃₅₎-mediated toxicity(Bachurin et al., 2001). As shown in FIG. 22C, Dimebon only affordedprotection at doses of 3 μM. Example 45 Compound did not loseneuroprotective activity even when diluted to low nanomolar levels.Dimebon has also been implicated in protecting mitochondria (Bachurin etal., 2003). We therefore compared Dimebon with Example 45 Compound inthe calcium-induced mitochondrial dissolution assay. Both compounds wereobserved to be active, and it was again observed that the relativepotency of Example 45 Compound was superior to Dimebon (FIG. 22D).Protection of mitochondrial membrane permeability was lost for Example45 Compound between the 10 and 1 nM doses, whereas that of Dimebon waslost between 10 and 1 μM.

Example 45 Compound and Dimebon were tested for binding to the H1histamine receptor. While Dimebon displayed high affinity for thisreceptor (IC50<100 nM), both enantiomers of Example 45 Compound displaylow H1 affinity (IC50>10 μM.

Effect of Example 45 Compound on Aged Rats

We turned to aged Fisher rats as a means of performing behavioral testscapable of assessing the potential benefits of Example 45 Compound onhippocampus-dependent learning. It is well established that normalrodent aging is associated with attenuation of hippocampal neurogenesis(Kuhn et al., 1996, Driscoll et al., 2006). Reduced neurogenesis in agedrats is likely related to increased neuronal apoptosis in the aged ratbrain (Martin et al., 2002; Kim et al., 2010). These changes have beenhypothesized to contribute to cognitive decline as a function ofterminal aging. We first evaluated whether Example 45 Compound wouldenhance hippocampal neurogenesis in aged rats as it does in adult mice.Rats were injected with a daily, IP dose of either 10 mg/kg of Example45 Compound or vehicle, coinjected with a daily dose of BrdU, and thensacrificed after 7 days for immunohistochemistry. As shown in FIG. 23A,compound-treated animals revealed a 500% increase in BrdU labeling inthe dentate gyms relative to vehicle-treated controls.Immunohistochemical staining with antibodies to doublecortin likewiserevealed a robust, compound-specific enrichment in this marker ofnewborn neurons. Having observed proneurogenic efficacy of Example 45Compound in this short term assay, we then tested whether prolongedadministration of Example 45 Compound might ameliorate age-relateddecline in cognition by subjecting 18-month-old rats to dailyadministration of either i 0 mg/kg of Example 45 Compound or vehicleonly for 2 months. Animals of both groups were further subjected toweekly IP administration of BrdU (50 mg/kg) for laterimmunohistochemical measurements of hippocampal neurogenesis. As acontrol, both Example 45 Compound- and vehicle-treated groups wereconfirmed to display equal ability to physically participate in thetask, and learn the task, as shown by decreased latency times to findthe hidden platform over the 5 day training period, both before andafter 2 months of treatment (FIG. 23B). Moreover, neither swim speed(FIG. 23C) nor locomotor activity (FIG. 23D) varied with age ortreatment paradigm. After 2 months of compound or vehicleadministration, cognitive ability was assessed blind to treatment groupby removing the goal platfonrl. Animals of the Example 45Compound-treated group retained a statistically significant improvementin ability to navigate to the region of the missing platfoml, asevidenced by performance in the probe test. As shown in FIG. 24A, whenthe platform was removed from the maze, rats treated with Example 45Compound crossed the precise location previously containing the platformsignificantly more often than vehicle-treated rats. Furthermore, Example45 Compound-treated rats spent a higher percentage of time in thegeneral goal area, defined as the quadrant previously containing theplatform, than vehicle-treated rats (35.5%±2.2% for Example 45 Compoundtreated, 28.1%±2.6% for vehicle treated, Student's t Test, p<0.02).

After behavioral testing, animals were sacrificed forimmunohistochemical detection of BrdU and CCSP3. As shown in FIG. 24B,the dentate gyms of rats exposed to Example 45 Compound showed a 3-foldhigher level of BrdU-positive neurons than that of the vehicle group.Moreover, Example 45 Compound-treated animals showed a statisticallysignificant reduction in the number of CCSP3-positive cells relative tovehicle controls (FIG. 24C). Unexpectedly, administration of Example 45Compound helped rats maintain stable body weight with aging, in contrastto vehicle-treated rats, whose weight declined steadily with age (FIG.24D). Example 45 Compound-mediated effects on body weight wereindependent of food intake (FIG. 23E), and treatment of aged rats withExample 45 Compound had no effect on postfasting blood glucose levels(FIG. 23E). It will be of interest to determine whether Example 45Compound-mediated preservation of body weight in aged rats operates viacentral or peripheral modes of action.

Example 45 Compound Protects Mitochondria

Knowing that P7C3 ameliorates the death of newborn neurons in thedentate gyms in living mice, we wondered whether its function mightrelate to mitochondrial integrity. Assays were established to testwhether P7C3 might protect cultured U2OS cells from calcium-inducedmitochondrial dissolution (Distelmaier et al., 2008).Tetramethylrhodamine methylester (TMRM) dye is sequestered by activemitochondria, and, when loaded with TMRM, vehicle-treated cells releasedthe dye within 15 rain of exposure to the calcium ionophor A23187. Bycontrast, dye release was fully prevented in cells exposed to as littleas 10 nM of P7C3 (FIG. 25). Compound loaown to be inactive in vivo werealso inactive in this assay (FIG. 25). Preservation of mitochondrialmembrane potential in this assay was observed for the R-enantiomer ofone compound (B), but not the S-enantiomer (C). Finally, protection ofmitochondrial membrane permeability was observed at an enhanced levelfor a compound variant, which also exhibited a high level ofproneurogenic activity (FIG. 25). Example 45 Compound, but not aninactive compound, was also capable of preserving mitochondrialintegrity in cultured primary cortical neurons (FIG. 25).

Example Compound 45 Normalizes Elevated Levels of Hippocampal Apoptosisin npas3^(−/−) Mice

Recognizing that reduced thickness of the npas3^(−/−) dentate gymsgranular layer could be attributed to increased apoptosis ofproliferating neural precursor cells, we examined the effect of Example45 Compound treatment on apoptosis in the hippocampus of npas3^(−/−)mice through immunohistochemical staining of CCSP3. After 12 days oforally delivered Example 45 Compound (20 mg/kg) to adult npas3−/− mice,a statistically significant reduction in CCSP3 staining was observed inthe dentate gyms. We thereby propose that Example 45 Compoundfacilitates repair of the granular layer of the dentate gyms innpas3^(−/−) mice by overcoming a genotype-specific enhancement inapoptosis.

Other Embodiments

This application claims the benefit of U.S. Provisional Application No.61/143,755, which is incorporated herein by reference in its entirety.The disclosure of U.S. Provisional Application No. 61/143,755 includes,but is not limited to:

-   -   methods for promoting postnatal mammalian neurotrophism in a        patient determined to be in need    -   thereof, comprising administering to the patient an effective        amount of a neurotrophic carbazole compound of formula 1:

-   -   wherein:    -   R₁-R₈ are each independently selected hydrogen, heteroatom,        heteroatom functional group, and optionally-substituted,        optionally heteroatom lower (C1-C6) alkyl;    -   R₉ is hydrogen or optionally-substituted, optionally heteroatom        lower (C1-C6) alkyl; and    -   R₁₀ and R₁₁ are each independently selected hydrogen,        optionally-substituted, optionally heteroatom C1-C6 alkyl,        optionally-substituted, optionally heteroatom C2-C6 alkenyl,        optionally-substituted, optionally heteroatom C2-C6 alkynyl, and        optionally-substituted, optionally heteroatom C6-C14 aryl,        including tautomers, stereoisomers and        pharmaceutically-acceptable salts thereof.    -   Unless otherwise noted, all structures depicted herein encompass        interconvertable tautomers as if each were separately depicted.    -   The invention encompasses all alternative combinations of        particular embodiments:        -   wherein R₁-R₈ are each independently selected hydrogen and            halide;        -   wherein R₁, R₂, R₄, R₅, R₇ and R₈ are hydrogen, and R₃ and            R₆ are halide, such as Cl, Br, I and F;        -   wherein R₉ is hydrogen;        -   wherein R₁₀ is hydrogen and R₁₁ is optionally-substituted,            optionally heteroatom C₆-C₁₄ aryl;        -   wherein R₁₀ and R₁₁ are joined to form a 5-7 membered,            optionally substituted heterocyclic ring;        -   wherein R₁₀ and R₁₁ are joined to form an optionally            substituted pyrrolidine or a piperidine;        -   wherein R₁₀ is hydrogen and R₁₁ is substituted phenyl, such            as halide- or C₁-C₆ alkoxy-phenyl, including para-, meta-,            or ortho positions;        -   wherein R₁₀ is hydrogen and R₁₁ is napthyl;        -   wherein the compound has a formula of Table 1 (herein) or            Table 2 (herein);        -   wherein the compound has formula 2:

-   -   -   -   wherein (a) at least one of R₁-R₈ is heteroatom,                optionally-substituted, or optionally heteroatom lower                (C1-C6) alkyl, and at least one of R₁-R₄ or at least one                of R₅-R₈ is different; or (b) R₉ is                optionally-substituted, optionally heteroatom lower                (C1-C6) alkyl;            -   further comprising the step of detecting a resultant                neurotrophism, particularly neurogenesis; and/or            -   further comprising the antecedent step of determining                that the patient has aberrant neurotrophism,                particularly aberrant neurogenesis, particularly                aberrant hippocampal neurogenesis, or a disease or                disorder associated therewith, particularly by detecting                and/or diagnosing the same.

The invention also provides novel pharmaceutical, particularly novelneurogenic, compositions in unit dosage comprising a disclosedneurotrophic carbazole not previously known or suggested to providepharmacological, particularly neurogenic, activity, or apharmaceutically-acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

The invention also provides disclosed novel neurotrophic carbazoles andpharmaceutically-acceptable salts thereof.

U.S. Provisional Application No. 61/143,755 further discloses:

The term “heteroatom” as used herein generally means any atom other thancarbon, hydrogen or oxygen. Preferred heteroatoms include oxygen (O),phosphorus (P), sulfur (S), nitrogen (N), silicon (S), arsenic (As),selenium (Se), and halogens, and preferred heteroatom functional groupsare haloformyl, hydroxyl, aldehyde, amine, azo, carboxyl, cyanyl,thocyanyl, carbonyl, halo, hydroperoxyl, imine, aldimine, isocyanide,iscyante, nitrate, nitrile, nitrite, nitro, nitroso, phosphate,phosphono, sulfide, sulfonyl, sulfo, and sulfhydryl.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which is fully saturated,having the number of carbon atoms designated (i.e. C1-C8 means one toeight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.

The term “alkenyl”, by itself or as part of another substituent, means astraight or branched chain, or cyclic hydrocarbon radical, orcombination thereof, which may be mono- or polyunsaturated, having thenumber of carbon atoms designated (i.e. C2-C8 means two to eightcarbons) and one or more double bonds. Examples of alkenyl groupsinclude vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl) and higher homologs and isomersthereof.

The term “alkynyl”, by itself or as part of another substituent, means astraight or branched chain hydrocarbon radical, or combination thereof,which may be mono- or polyunsaturated, having the number of carbon atomsdesignated (i.e. C2-C8 means two to eight carbons) and one or moretriple bonds. Examples of alkynyl groups include ethynyl, 1- and3-propynyl, 3-butynyl and higher homologs and isomers thereof.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from alkyl, as exemplified by—CH₂—CH₂—CH₂—CH₂-. Typically, an alkyl (or alkylene) group will havefrom 1 to 24 carbon atoms, with those groups having 10 or fewer carbonatoms being preferred in the invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingeight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and from one to three heteroatoms selectedfrom the group consisting of O, N, Si and S, wherein the nitrogen andsulfur atoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) O, N and S may be placed atany interior position of the heteroalkyl group. The heteroatom Si may beplaced at any position of the heteroalkyl group, including the positionat which the alkyl group is attached to the remainder of the molecule.Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatomsmay be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent means a divalent radical derived from heteroalkyl, asexemplified by —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. Forheteroalkylene groups, heteroatoms can also occupy either or both of thechain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino,alkylenediamino, and the like). Still further, for alkylene andheteroalkylene linking groups, no orientation of the linking group isimplied.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Accordingly, acycloalkyl group has the number of carbon atoms designated (i.e., C₃-C₈means three to eight carbons) and may also have one or two double bonds.A heterocycloalkyl group consists of the number of carbon atomsdesignated and from one to three heteroatoms selected from the groupconsisting of O, N, Si and S, and wherein the nitrogen and sulfur atomsmay optionally be oxidized and the nitrogen heteroatom may optionally bequaternized. Additionally, for heterocycloalkyl, a heteroatom can occupythe position at which the heterocycle is attached to the remainder ofthe molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include 1-(1,2,5,6-tetrahydropyrid-yl), 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” and “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include alkyl substituted with halogen atoms, which can be thesame or different, in a number ranging from one to (2 m′+1), where m′ isthe total number of carbon atoms in the alkyl group. For example, theterm “halo(C₁-C₄)alkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus,the term “haloalkyl” includes monohaloalkyl(alkyl substituted with onehalogen atom) and polyhaloalkyl(alkyl substituted with halogen atoms ina number ranging from two to (2 m′+1) halogen atoms, where m′ is thetotal number of carbon atoms in the alkyl group). The term“perhaloalkyl” means, unless otherwise stated, alkyl substituted with (2m′+1) halogen atoms, where m′ is the total number of carbon atoms in thealkyl group. For example the term “perhalo(C1-C4)alkyl” is meant toinclude trifluoromethyl, pentachloroethyl,1,1,1-trifluoro-2-bromo-2-chloroethyl and the like.

The term “acyl” refers to those groups derived from an organic acid byremoval of the hydroxy portion of the acid. Accordingly, acyl is meantto include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl,benzoyl and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon substituent which can be a single ringor multiple rings (up to three rings) which are fused together or linkedcovalently. Non-limiting examples of aryl groups include phenyl,1-naphthyl, 2-naphthyl, 4-biphenyl and 1,2,3,4-tetrahydronaphthalene.

The term heteroaryl,” refers to aryl groups (or rings) that contain fromzero to four heteroatoms selected from N, O, and S, wherein the nitrogenand sulfur atoms are optionally oxidized and the nitrogen heteroatom areoptionally quaternized. A heteroaryl group can be attached to theremainder of the molecule through a heteroatom. Non-limiting examples ofheteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl,4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyland 6-quinolyl.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) is meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (as well as thosegroups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl,alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl andheterocycloalkenyl) can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN and —NO₂, in a number rangingfrom zero to three, with those groups having zero, one or twosubstituents being particularly preferred. R′, R″ and R′″ eachindependently refer to hydrogen, unsubstituted (C1-C8)alkyl andheteroalkyl, unsubstituted aryl, aryl substituted with one to threehalogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, oraryl-(C1-C4)alkyl groups. When R′ and R″ are attached to the samenitrogen atom, they can be combined with the nitrogen atom to form a 5-,6- or 7-membered ring. For example, —NR′R″ is meant to include1-pyrrolidinyl and 4-morpholinyl. Typically, an alkyl or heteroalkylgroup will have from zero to three substituents, with those groupshaving two or fewer substituents being preferred in the invention. Morepreferably, an alkyl or heteroalkyl radical will be unsubstituted ormonosubstituted. Most preferably, an alkyl or heteroalkyl radical willbe unsubstituted. From the above discussion of substituents, one ofskill in the art will understand that the term “alkyl” is meant toinclude groups such as trihaloalkyl (e.g., —CF₃ and —CH₂CF₃).

Preferred substituents for the alkyl and heteroalkyl radicals areselected from: —OR′, ═O, —NR′R″, —SR′, halogen, —SiR′R″R′″, —OC(O)R′,—C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′,—NR′—SO₂NR″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN and —NO₂,where R′ and R″ are as defined above. Further preferred substituents areselected from: —OR′, ═O, —NR′R″, halogen, —OC(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′—SO₂NR″R′″, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN and —NO₂.

Similarly, substituents for the aryl and heteroaryl groups are variedand selected from: halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN,—NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO2R′,—NR′−C(O)NR″R′“, —NR′—SO₂NR″R′”, —NH—C(NH2)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —N₃, —CH(Ph)₂,perfluoro(C₁-C₄)alko-xy and perfluoro (C1-C4)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, (C1-C8)alkyl and heteroalkyl, unsubstituted aryl andheteroaryl, (unsubstituted aryl)-(C1-C4)alkyl and (unsubstitutedaryl)oxy-(C1-C4)alkyl. When the aryl group is1,2,3,4-tetrahydronaphthalene, it may be substituted with a substitutedor unsubstituted (C3-C7)spirocycloalkyl group. The(C3-C7)spirocycloalkyl group may be substituted in the same manner asdefined herein for “cycloalkyl”. Typically, an aryl or heteroaryl groupwill have from zero to three substituents, with those groups having twoor fewer substituents being preferred in the invention. In oneembodiment of the invention, an aryl or heteroaryl group will beunsubstituted or monosubstituted. In another embodiment, an aryl orheteroaryl group will be unsubstituted.

Preferred substituents for aryl and heteroaryl groups are selected from:halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″,—C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R,—N₃, —CH(Ph)₂, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, whereR′ and R″ are as defined above. Further preferred substituents areselected from: halogen, —OR′, —OC(O)R′, —NR′R″, —R′, —CN, —NO₂, —CO₂R′,—CONR′R″, —NR″C(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R,perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl.

The substituent —CO₂H, as used herein, includes bioisostericreplacements therefor; see, e.g., The Practice of Medicinal Chemistry;Wermuth, C. G., Ed.; Academic Press: New York, 1996; p. 203.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula -A-(CH2)r-B-,wherein A and B are independently —CH₂—, —O—, —NH—, —S—, —S(O)—,—S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integer of from 1 to3. One of the single bonds of the new ring so formed may optionally bereplaced with a double bond. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula —(CH₂)s-X—(CH₂)t-, where s and t areindependently integers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—,—S(O)₂—, or —S(O)₂NR′—. The substituent R′ in —NR′— and —S(O)₂NR′— isselected from hydrogen or unsubstituted (C1-C6)alkyl.

What is claimed is:
 1. A method for treating traumatic brain injurycomprising: administering to a subject in need thereof an effectiveamount of a compound, or a pharmaceutically acceptable salt thereof,wherein the compound has the following formula:

wherein: R³ and R⁶ are each independently selected from halo, C₁-C₆alkyl, C₂-C₆ alkynyl, cyclopropyl, —N₃, and cyano; A is CR^(A1)R^(A2),wherein R^(A1) is selected from hydrogen, halo, C₁-C₃ alkyl, and OR⁹,and R^(A2) is selected from halo, C₁-C₃ alkyl, and OR⁹; Z is selectedfrom —NHR¹⁰; —N(CH₃)R¹¹; —OR¹²; and —S(O)_(n)R¹³, wherein n is 0, 1, or2; R⁹ is hydrogen or C₁-C₃ alkyl that is optionally substituted withhydroxyl or C₁-C₃ alkoxy; R¹⁰, R¹¹, R¹² and R¹³ are each independentlyselected from: (a) C₆-C₁₀ aryl that is optionally substituted with 1 to4R^(b); or (b) heteroaryl containing from 6-14 ring atoms, wherein from1-6 of the ring atoms are independently selected from N, NH, N(C₁-C₃alkyl), O, and S; and wherein said heteroaryl is optionally substitutedwith from 1 to 4R^(b); R^(b) at each occurrence is independentlyselected from the substituents delineated in (aa) through (dd) below:(aa) C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆thiohaloalkoxy; —O—(CH₂)₁₋₃—[O(CH₂)₁₋₃]₁₋₃—H; C₁-C₆ alkyl, C₁-C₆haloalkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl);(bb) halo; hydroxyl; cyano; nitro; —NH₂; azido; sulfhydryl; C₂-C₆alkenyl; C₂-C₆ alkynyl; —C(O)H; —C(O)(C₁-C₆ alkyl); —C(O)(C₁-C₆haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl); —C(O)NH₂; —C(O)NH(C₁-C₆ alkyl);C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl); —SO₂NH₂; —SO₂NH(C₁-C₆ alkyl);—SO₂N(C₁-C₆ alkyl)₂; (cc) C₃-C₆ cycloalkyl or heterocyclyl containingfrom 5 to 6 ring atoms, wherein from 1 to 2 of the ring atoms of theheterocyclyl is independently selected from N, NH, N(C₁-C₆ alkyl),NC(O)(C₁-C₆ alkyl), O, and S; and (dd) phenyl or heteroaryl containingfrom 5 to 6 ring atoms, wherein from 1 to 2 of the ring atoms of theheteroaryl is independently selected from N, NH, N(C₁-C₃ alkyl), O, andS; wherein each of said phenyl and heteroaryl is optionally substitutedwith from 1 to 3 substituents independently selected from halo;hydroxyl; cyano; nitro; —NH₂; —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy;C₁-C₆ thiohaloalkoxy; C₁-C₆ alkyl, and C₁-C₆ haloalkyl; wherein when R³and R⁶ are both halo, one of R^(A1) and R^(A2) is OH and the other ishydrogen, Z is —NHR¹⁰, and R¹⁰ is C₆-C₁₀ aryl that is optionallysubstituted with 1 to 4R^(b), then R¹⁰ is unsubstituted phenyl or phenylsubstituted with 1R^(b).
 2. The method of claim 1, wherein the carbonattached to R^(A1) and R^(A2) is substituted with four differentsubstituents, and is (R) or (S) configured.
 3. The method of claim 2,wherein the compound or salt is (+) (dextrorotatory) or (−)(levororotatory).
 4. The method of claim 1, wherein the effective amountof the compound or salt reduces neuron cell death.
 5. The method ofclaim 1, wherein the compound is selected from:1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylthio)propan-2-ol;N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline;N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-methoxypropyl)-3-methoxyaniline;1-(3,6-Dimethyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;1-(3-Bromo-6-methyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;1-(3,6-Dichloro-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;1-(3,6-Dibromo-9H-pyrido[3,4-b]indol-9-yl)-3-(phenylamino)propan-2-ol;1-(3-Azidophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;1,3-Bis(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;1-(9H-Carbazol-9-yl)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-2-ylamino)propan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-((3-methoxyphenyl)(methyl)-amino)propan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyrimidin-2-ylamino)propan-2-ol;N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxy-N-methylaniline;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-ethoxyphenylamino)propan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfinyl)propan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;1-(3-bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-3-ylamino)propan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-4-ylamino)propan-2-ol;N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2,2-difluoropropyl)-3-methoxyaniline;1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;(S)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;(R)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;3,6-dibromo-9-(2-fluoro-3-phenoxypropyl)-9H-carbazole;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-2-methylpropan-2-ol;1-(4-azidophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;1-(3-azido-6-bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(4-methoxyphenoxy)propan-2-ol;1-(3,6-dichloro-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;3,6-dibromo-9-(2-fluoro-3-(phenylsulfonyl)propyl)-9H-carbazole;(S)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;(R)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;1-(3,6-dicyclopropyl-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;1-(3,6-diiodo-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;1-(3,6-diethynyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;9-(2-hydroxy-3-(3-methoxyphenylamino)propyl)-9H-carbazole-3,6-dicarbonitrile;N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)aniline;3,6-dibromo-9-(2,2-difluoro-3-phenoxypropyl)-9H-carbazole;N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-methoxyaniline;N-(2-bromo-3-(3,6-dibromo-9H-carbazol-9-yl)propyl)-N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide;Ethyl2-(4-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropylamino)phenoxy)acetate;andN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-(2-(2-methoxyethoxy)ethoxy)aniline.6. The method of claim 1, wherein the compound is selected from:1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylthio)propan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfinyl)propan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline;N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxy-N-methylaniline;N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-methoxypropyl)-3-methoxyaniline;1-(3-bromo-6-methyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-2-ylamino)propan-2-ol;(R)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;3,6-dibromo-9-(2-fluoro-3-phenoxypropyl)-9H-carbazole;1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-2-methylpropan-2-ol;1-(4-azidophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;3,6-dibromo-9-(2-fluoro-3-(phenylsulfonyl)propyl)-9H-carbazole;(S)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;(R)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;9-(2-hydroxy-3-(3-methoxyphenylamino)propyl)-9H-carbazole-3,6-dicarbonitrile;N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)aniline; andN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-methoxyaniline. 7.The method of claim 1, wherein the compound is selected from:N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline;N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxy-N-methylaniline;3,6-dibromo-9-(2-fluoro-3-phenoxypropyl)-9H-carbazole;3,6-dibromo-9-(2-fluoro-3-(phenylsulfonyl)propyl)-9H-carbazole;N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)aniline; andN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-methoxyaniline. 8.The method of claim 1, wherein the compound isN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline. 9.A method for treating traumatic brain injury comprising: administeringto a subject in need thereof an effective amount of a compound, or apharmaceutically acceptable salt thereof, wherein the compound has thefollowing formula:

wherein R³ and R⁶ are each independently selected from halo, CH₃,ethynyl, cyclopropyl, —N₃, and cyano; R^(A1) and R^(A2) are eachindependently selected from hydrogen, halo, CH₃, and OR⁹, wherein one ofR^(A1) and R^(A2) is halo or OR⁹; Z is selected from —NHR¹⁰; —N(CH₃)R¹¹;—OR¹²; and —S(O)_(n)R¹³, wherein n is 0, 1, or 2; R⁹ is hydrogen orC₁-C₃ alkyl that is optionally substituted with hydroxyl or C₁-C₃alkoxy; R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from: (a)C₆-C₁₀ aryl that is optionally substituted with 1 to 4R^(b); or (b)heteroaryl containing from 6-14 ring atoms, wherein from 1-6 of the ringatoms are independently selected from N, NH, N(C₁-C₃ alkyl), O, and S;and wherein said heteroaryl is optionally substituted with from 1 to41e; R^(b) at each occurrence is independently selected from thesubstituents delineated in (aa) through (dd) below: (aa) C₁-C₆ alkoxy;C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆ thiohaloalkoxy;—O—(CH₂)₁₋₃—[O(CH₂)₁₋₃]₁₋₃—H; C₁-C₆ alkyl, C₁-C₆ haloalkyl, —NH(C₁-C₆alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl); (bb) halo; hydroxyl;cyano; nitro; —NH₂; azido; sulfhydryl; C₂-C₆ alkenyl; C₂-C₆ alkynyl;—C(O)H; —C(O)(C₁-C₆ alkyl); —C(O)(C₁-C₆ haloalkyl); C(O)OH; —C(O)O(C₁-C₆alkyl); —C(O)NH₂; —C(O)NH(C₁-C₆ alkyl); C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆alkyl); —SO₂NH₂; —SO₂NH(C₁-C₆ alkyl); —SO₂N(C₁-C₆ alkyl)₂; (cc) C₃-C₆cycloalkyl or heterocyclyl containing from 5 to 6 ring atoms, whereinfrom 1 to 2 of the ring atoms of the heterocyclyl is independentlyselected from N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S; and(dd) phenyl or heteroaryl containing from 5 to 6 ring atoms, whereinfrom 1 to 2 of the ring atoms of the heteroaryl is independentlyselected from N, NH, N(C₁-C₃ alkyl), O, and S; wherein each of saidphenyl and heteroaryl is optionally substituted with from 1 to 3substituents independently selected from halo; hydroxyl; cyano; nitro;—NH₂; —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), C₁-C₆alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆ thiohaloalkoxy; C₁-C₆alkyl, and C₁-C₆ haloalkyl; wherein when R³ and R⁶ are both halo, one ofR^(A1) and R^(A2) is OH and the other is hydrogen, Z is —NHR¹⁰, and R¹⁰is C₆-C₁₀ aryl that is optionally substituted with 1 to 4R^(b), then R¹⁰is unsubstituted phenyl or phenyl substituted with 1R^(b).
 10. Themethod of claim 9, wherein the carbon attached to R^(A1) and R^(A2) issubstituted with four different substituents, and is (R) or (S)configured.
 11. The method of claim 10, wherein the compound or salt is(+) (dextrorotatory) or (−) (levororotatory).
 12. The method of claim 9,wherein the effective amount of the compound or salt reduces neuron celldeath.
 13. A method for treating traumatic brain injury comprising:administering to a subject in need thereof an effective amount of acompound, or a pharmaceutically acceptable salt thereof, wherein thecompound has having the following formula:

wherein: Z is selected from —NHR¹⁰; —N(CH₃)R¹¹; —OR¹²; and —S(O)_(n)R¹³,wherein n is 0, 1, or 2; R¹⁰, R¹¹, R¹² and R¹³ are each independentlyselected from: (a) C₆-C₁₀ aryl that is optionally substituted with 1 to4R^(b); or (b) heteroaryl containing from 6-14 ring atoms, wherein from1-6 of the ring atoms are independently selected from N, NH, N(C₁-C₃alkyl), O, and S; and wherein said heteroaryl is optionally substitutedwith from 1 to 4R^(b); R^(b) at each occurrence is independentlyselected from the substituents delineated in (aa) through (dd) below:(aa) C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy; C₁-C₆thiohaloalkoxy; —O—(CH₂)₁₋₃—[O(CH₂)₁₋₃]₁₋₃—H; C₁-C₆ alkyl, C₁-C₆haloalkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl);(bb) halo; hydroxyl; cyano; nitro; —NH₂; azido; sulfhydryl; C₂-C₆alkenyl; C₂-C₆ alkynyl; —C(O)H; —C(O)(C₁-C₆ alkyl); —C(O)(C₁-C₆haloalkyl); C(O)OH; —C(O)O(C₁-C₆ alkyl); —C(O)NH₂; —C(O)NH(C₁-C₆ alkyl);C(O)N(C₁-C₆ alkyl)₂; —SO₂(C₁-C₆ alkyl); —SO₂NH₂; —SO₂NH(C₁-C₆ alkyl);—SO₂N(C₁-C₆ alkyl)₂; (cc) C₃-C₆ cycloalkyl or heterocyclyl containingfrom 5 to 6 ring atoms, wherein from 1 to 2 of the ring atoms of theheterocyclyl is independently selected from N, NH, N(C₁-C₆ alkyl),NC(O)(C₁-C₆ alkyl), O, and S; and (dd) phenyl or heteroaryl containingfrom 5 to 6 ring atoms, wherein from 1 to 2 of the ring atoms of theheteroaryl is independently selected from N, NH, N(C₁-C₃ alkyl), O, andS; wherein each of said phenyl and heteroaryl is optionally substitutedwith from 1 to 3 substituents independently selected from halo;hydroxyl; cyano; nitro; —NH₂; —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—NHC(O)(C₁-C₆ alkyl), C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ thioalkoxy;C₁-C₆ thiohaloalkoxy; C₁-C₆ alkyl, and C₁-C₆ haloalkyl.